MIG-15 is the sole Caenorhabditis elegans member of the GCK-IV subfamily of Ste20 kinases. In mammals and in vitro, MIG-15-like kinases can function as effectors of the small GTPase Rap2. To test this model in vivo, we compared phenotypes of mig-15 and rap-2 mutants. mig-15 mutants displayed severe defects in vulval morphogenesis, cell positioning, and locomotion. In contrast, rap-2 mutants were largely indistinguishable from wild type. These findings indicate that several developmental roles of MIG-15 occur independently of RAP-2, suggesting that additional upstream regulators, including other small GTPases or adhesion-related pathways, control MIG-15 activity in specific developmental contexts.
","acknowledgements":"We thank members of the Reiner lab for helpful discussions. The mig-15(gk5002) CRISPR/Cas9 gene replacement was generously provided by M. Edgley and D. Moerman at the C. elegans Gene Knockout Facility at the University of British Columbia, which was funded by CIHR (Canada) and the NIH (USA). Some strains were provided by the Caenorhabditis Genetics Center, which is funded by the NIH Office of Research Infrastructure Programs (P40 OD010440). R.A.F. was supported in part by the Saudi Arabian Cultural Mission.
","authors":[{"affiliations":["Texas A&M University"],"departments":["Vashisht College of Medicine"],"credit":["investigation","methodology","formalAnalysis","visualization","conceptualization"],"email":"fakieh@tamu.edu","firstName":"Razan","lastName":"Fakieh","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":"","orcid":"0000-0002-3511-2665"},{"affiliations":["University of Pennsylvania, Philadelphia, PA, US"],"departments":["Department of Genetics"],"credit":["formalAnalysis","investigation","conceptualization","visualization"],"email":"ranjana@caltech.edu","firstName":"Ranjana","lastName":"Kishore","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"000-0002-1478-7671"},{"affiliations":["University of Pennsylvania, Philadelphia, PA, US"],"departments":["Department of Genetics"],"credit":["conceptualization","fundingAcquisition","project","supervision","writing_reviewEditing","formalAnalysis","visualization"],"email":"sundaram@pennmedicine.upenn.edu","firstName":"Meera","lastName":"Sundaram","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"0000-0002-2940-8750"},{"affiliations":["Texas A&M University","Texas A&M Health Science Center"],"departments":["Vashisht College of Medicine","Institute of Biosciences and Technology"],"credit":["conceptualization","formalAnalysis","fundingAcquisition","investigation","methodology","project","supervision","visualization","writing_originalDraft","writing_reviewEditing"],"email":"dreiner@tamu.edu","firstName":"David","lastName":"Reiner","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"0000-0002-0344-7161"}],"awards":[{"awardId":"R35 GM144237","funderName":"National Institutes of Health (United States)","awardRecipient":"David J. Reiner"},{"awardId":"R03 CA289854 ","funderName":"National Cancer Institute (United States)","awardRecipient":"David J. Reiner"},{"awardId":"R35 GM136315 ","funderName":"National Institutes of Health (United States)","awardRecipient":"Meera V. Sundaram"},{"awardId":"R01 GM058540","funderName":"National Institutes of Health (United States)","awardRecipient":"Meera V. Sundaram"}],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"","image":{"url":"https://portal.micropublication.org/uploads/cb1f537b0037af5a3f88beadda2e7011.png"},"imageCaption":"(A-C) Representative DIC photomicrographs of P6.px cells and the AC in mid-L3 animals used for assessing centering of the AC and the presumptive 1˚ lineage. Arrowheads indicate anchor cells (ACs) and brackets indicate P6.p daughters P6.pa and P6.px. (A) Wild type, (B) mig-15(rh148), and (C) rap-2(re400). (D-F) Schematics of P6.px centering on the AC for the same genotypes as A, B, C, respectively. (G-I) Representative DIC photomicrographs of vulval morphogenesis at the mid-L4 stage for the same genotypes as A, B, C, respectively. (J) Quantification of displacement of the midline between P6.pa and P6.pp from the midline of the AC reveals a strong defect in the mig-15 but not rap-2 mutants shown in A-F. (K) A radial locomotion assay of rap-2 vs. mig-15 mutants revealed severe locomotion defects in mig-15 mutants but none in rap-2 mutants. Distance shown is in mm from the origin at which animals were placed vs. final position after 20 minutes on 10 cm plates. N = 30 for each genotype. (L) DIC analysis of the wild type vs. rap-2 and mig-15 mutants for Vulvaless (Vul) and Abnormal (Abn) phenotypes (see Methods). ‡ These data were also presented in Fakieh and Reiner, 2025. ∞rhIs15 is a MIG-15::GFP over-expressing (OE) integrated transgene from Xiaoping Zhu and Edward Hedgecock (Zhu, 1998). [RDJ1] §A small percentage (< 20%) of these animals showed multiple invaginations. F76% of these animals showed multiple invaginations. (M) Cell lineage analysis of P5.px, P6.px and P7.px cell divisions in vulval development during the late L3 stage. mig-15 mutants consistently show defects in the axes of this final cell division. The nomenclature used to describe the plane of cell divisions is L= longitudinal, T = transverse, O = oblique, N = no division. ANOVA was used for statistical analysis. **** represents p ≤ 0.0001, * represents p ≤ 0.05.
[RDJ1]Check formatting against Micropub guidelines
","imageTitle":"mig-15 mutants reveal vulval and locomotion defects not observed in rap-2 mutants
","methods":"Animal handling. All strains were derived from the N2 Bristol wild type. Animals were grown at 20 ˚C on OP50 E. coli seeded on NGM plates. Nomenclature was as described (Tuli, Daul, & Schedl, 2018). Wormbase and the Alliance of Genome Resources were both used (Sternberg et al., 2024).
The rap-2(gk11) knockout consortium deletion was backcrossed 5x to the wild type, rap-2(re400) is a STOP-IN disruption generated via CRISPR and rap-2(miz19dn) is a dominant negative mutation generated by CRISPR (Chen et al., 2018; Fakieh & Reiner, 2025). mig-15(rh148), mig-15(mu327) and mig-15(mu342) are kinase domain missense alleles, mig-15(gk5002) is a gene replacement, and mig-15(rh326) and mig-15(rh80) are nonsense alleles, all published previously (Fakieh & Reiner, 2025).
Imaging. Mid-L3, and mid-L4 animals were mounted on 3% agar pads containing 10 mM sodium azide as described (Sulston & Horvitz, 1977). Animals were scored using Differential Interference Contrast (DIC)/Nomarski optics on a Nikon Eclipse Ni microscope. Images were captured with an Andor Zyla camera and analyzed using Nikon NIS-Elements AR 4.20.00 software.
AC-VPC Centering assay. Animals were imaged using DIC microscopy at the Pn.px stage. Using the Nikon NIS Elements Advanced Research software, we measured the distance in microns between center of the AC nucleus and the mid-point between nuclei of the P6.pa and P6.pp daughter cells of P6.p.
VPC lineaging: The cell division planes of P5.pxx, P6.pxx and P7.pxx were observed by DIC/Nomarski microscopy. Nomenclature used to describe the polarity of cell divisions was L = longitudinal, T = transverse, O = oblique, and N = no division (Sternberg & Horvitz, 1986). By the L4 stage, vulval cell divisions and the invagination are normally complete. The numbers of vulval and non-vulval VPC descendants were counted to assess defects in cell-fate specification. Identities of individual nuclei were inferred based on their position and morphology and axes of final vulval divisions were determined by direct observation.
Radial locomotion assay. Locomotion was assayed as described (Mardick et al., 2021; Reiner, Newton, Tian, & Thomas, 1999; Reiner et al., 2006). Briefly, hermaphrodite adults without eggs were placed in the center of a 10-cm plate with a three-day evenly distributed lawn of OP50 E. coli and the origin was marked. Animals were allowed to move freely on the plate for 20 min at 20 ˚C. The plates were then transferred to -20 ˚C for 5 min to arrest movement. The final location of each animal was marked and the radial distance from the origin to the final point was measured to the nearest half mm. Statistical analysis was performed using Mann-Whitney U test and ANOVA (see figure legends for P values).
","reagents":"Strains used
All strains but NJ824 used for this study are described in (Fakieh & Reiner, 2025).
DV3054 rap-2(gk11) (5x backcrossed to N2)
DV3999 mig-15(gk5002 gkIs267[mig-15::myo-2p>GFP::mig-15])
","patternDescription":"MIG-15 is the sole Caenorhabditis elegans representative of the GCK-IV subfamily of Ste20 S/T kinases, which is conserved across metazoans. These proteins consist of an N-terminal Ste20 kinase domain, a long central proline-rich linker, and a C-terminal CNH domain (Citron-NIK Homology) (Chuang et al., 2016; Dan et al., 2001; Delpire, 2009). The Drosophila ortholog is Misshapen (Msn) and the mammalian orthologs are MAP4K4 (HGK/NIK), MAP4K6 (MINK1), and MAP4K7 (TNIK) (Bunardi et al., 2025). (NRK/NESK, sometimes referred to as MAP4K8, is generally not included in this group because its sequence is more divergent and expression is enriched in placenta (Denda et al., 2011), whereas the other GCK-IV kinases are broadly expressed.) The paralogous GCK-I subfamily of Ste20 kinases, consisting of C. elegans GCK-2, Drosophila Happyhour (Hppy) and mammalian MAP4K1,2,3,5, is structurally similar but functionally distinct.
MIG-15 in C. elegans regulates diverse morphogenetic and developmental processes (Chapman et al., 2008; Crawley et al., 2017; DaCunha et al., 2025; Huynh et al., 2026; Poinat et al., 2002; Shakir et al., 2006; Teuliere et al., 2011; Yang et al., 2014). Similar roles have been defined for Drosophila Msn (Kline et al., 2018; Paricio et al., 1999; Ruan et al., 2002; Su et al., 2000; Su et al., 1998).
The small GTPase Rap2 has been shown in mammalian systems and in vitro to bind or be phenotypically associated with MIG-15-like proteins of the GCK-IV subfamily. These findings indicate that, in mammals, GCK-IV Ste20 kinases can function as effectors of Rap2 (Gloerich et al., 2012; Hussain et al., 2010; Machida et al., 2004; Meng et al., 2018; Nonaka et al., 2008; Pannekoek et al., 2013; Taira et al., 2004). Recent studies make phenotypic connections between Drosophila Rap2l and Msn (Roberto et al., 2025), as well as between C. elegans RAP-2 and MIG-15 in synaptic tiling (Chen et al., 2018) and cell fate induction (Fakieh and Reiner, 2025).
During our studies, we observed that mig-15 mutant animals exhibit morphogenetic defects – in body shape, locomotion, and vulva – while rap-2 mutant animals are superficially wild type. Such a discrepancy is unexpected for a small GTPase and its effector, which often share loss-of-function phenotypes. Consequently, we characterized phenotypic defects in mig-15 relative to rap-2 mutant animals. These studies used putative mig-15 null mutations (gk5002, rh80, rh326) and missense mutations in conserved residues in the kinase domain (rh148, mu327, mu342), and putative rap-2 null mutations (gk11, re400) and a dominant-negative allele (miz19) (see Methods). Results were consistent across the multiple alleles tested.
Six ventral vulval precursor cells (VPCs), P3.p through P8.p, are spaced along the ventral midline during early larval development. Signal from the Anchor Cell (AC) induces these VPCs to assume the 3˚-3˚-2˚-1˚-2˚-3˚ pattern of VPC fates with 99.8% accuracy (Braendle and Felix, 2008; Shin et al., 2019). P6.p, closest to the AC, typically assumes the 1˚ fate, while the neighboring P5.p and P7.p cells assume the 2˚ fate (Shin and Reiner, 2018). During the L2 and early L3 stages, prior to its induction to assume the 1˚ fate, P6.p migrates to be positioned ventral to the AC (Grimbert et al., 2016). When assayed after the first VPC division, the P6.p daughters P6.pa and P6.pp were frequently displaced in mig-15(rh148) animals. In contrast, the P6.p daughters P6.pa and P6.pp in rap-2(re400) animals were positioned with the same accuracy as in wild type (Figure 1 A-C, schematized in Figure 1D-F and quantified in Figure 1J). The mid-L4 invaginated vulva, prior to eversion, forms a stereotyped structure that is frequently defective in mig-15(rh148) and other mig-15 mutants, but not a rap-2 mutant (Figure 1G-I; see also (Shin et al., 2018), quantified in Figure 1L. These defects included missing vulva cells (Vul phenotype) and, more frequently, mis-positioned vulva cells (Abn phenotype, Figure 1H). Overexpression of mig-15 (with transgene rhIs15, see Methods) caused similar vulva defects (Figure 1L). Analysis of VPC cell lineages by examining planes of cell division at the Pn.pxx cell division revealed defects in mig-15 mutants (Figure 1M).
By visual inspection, mig-15 mutant animals move poorly, while rap-2 mutants move normally. To assess general nervous system function via locomotion (Mardick et al., 2021), we measured radial locomotion of animals placed at the center of a plate. rap-2 mutants moved normally, while mig-15 mutants exhibited severe locomotion defects (Figure 1K). The putative null mig-15 mutations (gk5002, rh80, rh326) confer marginally more severe locomotion defects than the missense mutations (rh148, mu327, mu342).
Given the established relationships between Rap2 and MIG-15/GCK-IV orthologs, it is striking to observe loss-of-function mig-15 mutant phenotypes not phenocopied by loss-of-function mutations in rap-2. Consequently, we entertain the possibility that RAP-2 activates MIG-15 in only a subset of MIG-15 functions. Alternatively, RAP-2 could function redundantly with other inputs to control MIG-15 in selected tissues. MIG-15 mutant morphogenetic defects resemble those caused by mutations in MIG-2/RhoG and CED-10/Rac, as well as their activating RhoGEF UNC-73/TRIO (Kishore and Sundaram, 2002). This phenotypic similarity hints that these Rho family GTPases could activate MIG-15 in particular developmental contexts, in contrast to the Ras family GTPase Rap2.
By yeast two-hybrid assay, the CNH domain of MIG-15 interacts with the cytoplasmic domains of INA-1 ⍺ and PAT-3 β integrin subunits, predicted to form a laminin-binding integrin (Poinat et al., 2002). These interactions were supported by in vitro assays and experiments in HeLa and COS cells (Poinat et al., 2002). Genetic interactions in C. elegans are consistent with MIG-15 and INA-1/PAT-3 acting in the same pathway in axon guidance and fasciculation.
Mammalian TRAF1 (TNF receptor associated factor; (Inoue et al., 2000)) binds TNIK/MAP4K7 as an activator during inflammatory response (Fu et al., 1999), suggesting C. elegans TRAF orthologs TRF-1 and/or TRF-2 (Nikonorova et al., 2025) as potential upstream inputs. A negative regulator of GCK-IV MIG-15 subfamily proteins is the SH2-SH3 domain adaptor protein NCK, which binds to the central proline-rich region to sequester the kinase (Su et al., 1997). Release from this inhibition could activate MIG-15 in selected tissues.
Our results demonstrate that MIG-15 controls multiple morphogenetic and developmental processes in C. elegans that are not detectably dependent on RAP-2. These findings suggest that additional upstream regulators contribute to MIG-15 function in vivo, as well as in other systems where MIG-15-like GCK-IV subfamily proteins perform important functions.
","references":[{"reference":"Braendle C, Félix MA. 2008. Plasticity and errors of a robust developmental system in different environments. Dev Cell 15(5): 714-24.
","pubmedId":"19000836","doi":""},{"reference":"Bunardi CS, Yeom M, Kosasih P, Han H, Wang W, Seo G. 2025. MAP4K signaling pathways in cancer: roles, mechanisms and therapeutic opportunities. Exp Mol Med 57(10): 2148-2156.
","pubmedId":"41034525","doi":""},{"reference":"Chapman JO, Li H, Lundquist EA. 2008. The MIG-15 NIK kinase acts cell-autonomously in neuroblast polarization and migration in C. elegans. Dev Biol 324(2): 245-57.
","pubmedId":"18840424","doi":""},{"reference":"Chen X, Shibata AC, Hendi A, Kurashina M, Fortes E, Weilinger NL, et al., Mizumoto K. 2018. Rap2 and TNIK control Plexin-dependent tiled synaptic innervation in C. elegans. Elife 7: 10.7554/eLife.38801.
","pubmedId":"30063210","doi":""},{"reference":"Chuang HC, Wang X, Tan TH. 2016. MAP4K Family Kinases in Immunity and Inflammation. Advances in Immunology : 277-314.
","pubmedId":"","doi":" 10.1016/bs.ai.2015.09.006"},{"reference":"Crawley O, Giles AC, Desbois M, Kashyap S, Birnbaum R, Grill B. 2017. A MIG-15/JNK-1 MAP kinase cascade opposes RPM-1 signaling in synapse formation and learning. PLoS Genet 13(12): e1007095.
","pubmedId":"29228003","doi":""},{"reference":"DaCunha S, Silverman GA, Schedl T, Pak SC, Fielder SM, Penny GM. 2025. Null Mutant mig-15(udn323) Shows Touch Receptor Neuron Migration Defects in C. elegans. MicroPubl Biol 2025: 10.17912/micropub.biology.001904.
","pubmedId":"41426950","doi":""},{"reference":"Dan I, Watanabe NM, Kusumi A. 2001. The Ste20 group kinases as regulators of MAP kinase cascades. Trends Cell Biol 11(5): 220-30.
","pubmedId":"11316611","doi":""},{"reference":"Delpire E. 2009. The mammalian family of sterile 20p-like protein kinases. Pflugers Arch 458(5): 953-67.
","pubmedId":"19399514","doi":""},{"reference":"Denda K, Nakao-Wakabayashi K, Okamoto N, Kitamura N, Ryu JY, Tagawa YI, et al., Komada M. 2011. Nrk, an X-linked protein kinase in the germinal center kinase family, is required for placental development and fetoplacental induction of labor. J Biol Chem 286(33): 28802-28810.
","pubmedId":"21715335","doi":""},{"reference":"Fakieh RA, Reiner DJ. 2025. RAP-2 and CNH-MAP4 Kinase MIG-15 confer resistance in bystander epithelium to cell-fate transformation by excess Ras or Notch activity. Proc Natl Acad Sci U S A 122(1): e2414321121.
","pubmedId":"39739816","doi":""},{"reference":"Fu CA, Shen M, Huang BC, Lasaga J, Payan DG, Luo Y. 1999. TNIK, a novel member of the germinal center kinase family that activates the c-Jun N-terminal kinase pathway and regulates the cytoskeleton. J Biol Chem 274(43): 30729-37.
","pubmedId":"10521462","doi":""},{"reference":"Gloerich M, ten Klooster JP, Vliem MJ, Koorman T, Zwartkruis FJ, Clevers H, Bos JL. 2012. Rap2A links intestinal cell polarity to brush border formation. Nat Cell Biol 14(8): 793-801.
","pubmedId":"22797597","doi":""},{"reference":"Grimbert S, Tietze K, Barkoulas M, Sternberg PW, Félix MA, Braendle C. 2016. Anchor cell signaling and vulval precursor cell positioning establish a reproducible spatial context during C. elegans vulval induction. Dev Biol 416(1): 123-135.
","pubmedId":"27288708","doi":""},{"reference":"Hussain NK, Hsin H, Huganir RL, Sheng M. 2010. MINK and TNIK differentially act on Rap2-mediated signal transduction to regulate neuronal structure and AMPA receptor function. J Neurosci 30(44): 14786-94.
","pubmedId":"21048137","doi":""},{"reference":"Huynh L, Fakieh RA, Hendrix C, Powell R, Reiner DJ. 2026. Canonical and Non-canonical Hippo signaling in C. elegans. Genetics: pii: iyag056. 10.1093/genetics/iyag056.
","pubmedId":"41746831","doi":""},{"reference":"Inoue Ji, Ishida T, Tsukamoto N, Kobayashi N, Naito A, Azuma S, Yamamoto T. 2000. Tumor necrosis factor receptor-associated factor (TRAF) family: adapter proteins that mediate cytokine signaling. Exp Cell Res 254(1): 14-24.
","pubmedId":"10623461","doi":""},{"reference":"Kishore RS, Sundaram MV. 2002. ced-10 Rac and mig-2 function redundantly and act with unc-73 trio to control the orientation of vulval cell divisions and migrations in Caenorhabditis elegans. Dev Biol 241(2): 339-48.
","pubmedId":"11784116","doi":""},{"reference":"Kline A, Curry T, Lewellyn L. 2018. The Misshapen kinase regulates the size and stability of the germline ring canals in the Drosophila egg chamber. Dev Biol 440(2): 99-112.
","pubmedId":"29753016","doi":""},{"reference":"Machida N, Umikawa M, Takei K, Sakima N, Myagmar BE, Taira K, et al., Kariya K. 2004. Mitogen-activated protein kinase kinase kinase kinase 4 as a putative effector of Rap2 to activate the c-Jun N-terminal kinase. J Biol Chem 279(16): 15711-4.
","pubmedId":"14966141","doi":""},{"reference":"Mardick JI, Rasmussen NR, Wightman B, Reiner DJ. 2021. Parallel Rap1>RalGEF>Ral and Ras signals sculpt the C. elegans nervous system. Dev Biol 477: 37-48.
","pubmedId":"33991533","doi":""},{"reference":"Meng Z, Qiu Y, Lin KC, Kumar A, Placone JK, Fang C, et al., Guan KL. 2018. RAP2 mediates mechanoresponses of the Hippo pathway. Nature 560(7720): 655-660.
","pubmedId":"30135582","doi":""},{"reference":"Nikonorova IA, desRanleau E, Jacobs KC, Saul J, Walsh JD, Wang J, Barr MM. 2025. Polycystins recruit cargo to distinct ciliary extracellular vesicle subtypes in C. elegans. Nat Commun 16(1): 2899.
","pubmedId":"40180912","doi":""},{"reference":"Nonaka H, Takei K, Umikawa M, Oshiro M, Kuninaka K, Bayarjargal M, et al., Kariya KI. 2008. MINK is a Rap2 effector for phosphorylation of the postsynaptic scaffold protein TANC1. Biochem Biophys Res Commun 377(2): 573-578.
","pubmedId":"18930710","doi":""},{"reference":"Pannekoek WJ, Linnemann JR, Brouwer PM, Bos JL, Rehmann H. 2013. Rap1 and Rap2 antagonistically control endothelial barrier resistance. PLoS One 8(2): e57903.
","pubmedId":"23469100","doi":""},{"reference":"Paricio N, Feiguin F, Boutros M, Eaton S, Mlodzik M. 1999. The Drosophila STE20-like kinase misshapen is required downstream of the Frizzled receptor in planar polarity signaling. EMBO J 18(17): 4669-78.
","pubmedId":"10469646","doi":""},{"reference":"Poinat P, De Arcangelis A, Sookhareea S, Zhu X, Hedgecock EM, Labouesse M, Georges-Labouesse E. 2002. A conserved interaction between beta1 integrin/PAT-3 and Nck-interacting kinase/MIG-15 that mediates commissural axon navigation in C. elegans. Curr Biol 12(8): 622-31.
","pubmedId":"11967148","doi":""},{"reference":"Reiner DJ, Newton EM, Tian H, Thomas JH. 1999. Diverse behavioural defects caused by mutations in Caenorhabditis elegans unc-43 CaM kinase II. Nature 402(6758): 199-203.
","pubmedId":"10647014","doi":""},{"reference":"Reiner DJ, Weinshenker D, Tian H, Thomas JH, Nishiwaki K, Miwa J, et al., Garcia LR. 2006. Behavioral genetics of caenorhabditis elegans unc-103-encoded erg-like K(+) channel. J Neurogenet 20(1-2): 41-66.
","pubmedId":"16807195","doi":""},{"reference":"Roberto GM, Boutet A, Keil S, Del Guidice E, Duramé E, Tremblay MG, et al., Emery G. 2025. Tao and Rap2l ensure proper Misshapen activation and levels during Drosophila border cell migration. Dev Cell 60(1): 119-132.e6.
","pubmedId":"39393350","doi":""},{"reference":"Ruan W, Long H, Vuong DH, Rao Y. 2002. Bifocal is a downstream target of the Ste20-like serine/threonine kinase misshapen in regulating photoreceptor growth cone targeting in Drosophila. Neuron 36(5): 831-42.
","pubmedId":"12467587","doi":""},{"reference":"Shakir MA, Gill JS, Lundquist EA. 2006. Interactions of UNC-34 Enabled with Rac GTPases and the NIK kinase MIG-15 in Caenorhabditis elegans axon pathfinding and neuronal migration. Genetics 172(2): 893-913.
","pubmedId":"16204220","doi":""},{"reference":"Shin H, Braendle C, Monahan KB, Kaplan REW, Zand TP, Mote FS, Peters EC, Reiner DJ. 2019. Developmental fidelity is imposed by genetically separable RalGEF activities that mediate opposing signals. PLoS Genet 15(5): e1008056.
","pubmedId":"31086367","doi":""},{"reference":"Shin H, Kaplan REW, Duong T, Fakieh R, Reiner DJ. 2018. Ral Signals through a MAP4 Kinase-p38 MAP Kinase Cascade in C. elegans Cell Fate Patterning. Cell Rep 24(10): 2669-2681.e5.
","pubmedId":"30184501","doi":""},{"reference":"Shin H, Reiner DJ. 2018. The Signaling Network Controlling C. elegans Vulval Cell Fate Patterning. J Dev Biol 6(4): 10.3390/jdb6040030.
","pubmedId":"30544993","doi":""},{"reference":"Sternberg PW, Horvitz HR. 1986. Pattern formation during vulval development in C. elegans. Cell 44(5): 761-72.
","pubmedId":"3753901","doi":""},{"reference":"Sternberg PW, Van Auken K, Wang Q, Wright A, Yook K, Zarowiecki M, et al., Stein L. 2024. WormBase 2024: status and transitioning to Alliance infrastructure. Genetics 227(1): 10.1093/genetics/iyae050.
","pubmedId":"38573366","doi":""},{"reference":"Su YC, Han J, Xu S, Cobb M, Skolnik EY. 1997. NIK is a new Ste20-related kinase that binds NCK and MEKK1 and activates the SAPK/JNK cascade via a conserved regulatory domain. EMBO J 16(6): 1279-90.
","pubmedId":"9135144","doi":""},{"reference":"Su YC, Maurel-Zaffran C, Treisman JE, Skolnik EY. 2000. The Ste20 kinase misshapen regulates both photoreceptor axon targeting and dorsal closure, acting downstream of distinct signals. Mol Cell Biol 20(13): 4736-44.
","pubmedId":"10848599","doi":""},{"reference":"Su YC, Treisman JE, Skolnik EY. 1998. The Drosophila Ste20-related kinase misshapen is required for embryonic dorsal closure and acts through a JNK MAPK module on an evolutionarily conserved signaling pathway. Genes Dev 12(15): 2371-80.
","pubmedId":"9694801","doi":""},{"reference":"Sulston JE, Horvitz HR. 1977. Post-embryonic cell lineages of the nematode, Caenorhabditis elegans. Dev Biol 56(1): 110-56.
","pubmedId":"838129","doi":""},{"reference":"Taira K, Umikawa M, Takei K, Myagmar BE, Shinzato M, Machida N, et al., Kariya K. 2004. The Traf2- and Nck-interacting kinase as a putative effector of Rap2 to regulate actin cytoskeleton. J Biol Chem 279(47): 49488-96.
","pubmedId":"15342639","doi":""},{"reference":"Teulière J, Gally C, Garriga G, Labouesse M, Georges-Labouesse E. 2011. MIG-15 and ERM-1 promote growth cone directional migration in parallel to UNC-116 and WVE-1. Development 138(20): 4475-85.
","pubmedId":"21937599","doi":""},{"reference":"Tuli MA, Daul A, Schedl T. 2018. Caenorhabditis nomenclature. WormBook 2018: 1-14.
","pubmedId":"29722207","doi":""},{"reference":"Yang Y, Lee WS, Tang X, Wadsworth WG. 2014. Extracellular matrix regulates UNC-6 (netrin) axon guidance by controlling the direction of intracellular UNC-40 (DCC) outgrowth activity. PLoS One 9(5): e97258.
","pubmedId":"24824544","doi":""},{"reference":"Zhu, X. (1998). MIG-15, a NIK ortholog of the STE20 family of serine/threonine protein kinases, is involved in cell migration and cell signaling in C. elegans. [Dissertation]. [Baltimore (CA)]: John Hopkins University, 1989.
","pubmedId":"","doi":""}],"title":"RAP-2-independent roles for C. elegans MIG-15
","reviews":[{"reviewer":{"displayName":"Andrew Chisholm"},"openAcknowledgement":false,"status":{"submitted":true}}],"curatorReviews":[{"curator":{"displayName":"KJ Yook"},"openAcknowledgement":false,"submitted":"1778126597109"}]},{"id":"f0ffdb8c-67e8-471d-97c2-950817203c81","decision":"accept","abstract":"MIG-15 is the sole Caenorhabditis elegans member of the GCK-IV subfamily of Ste20 kinases. In mammals and in vitro, MIG-15-like kinases can function as effectors of the small GTPase Rap2. To test this model in vivo, we compared phenotypes of mig-15 and rap-2 mutants. mig-15 mutants displayed severe defects in vulval morphogenesis, cell positioning, and locomotion. In contrast, rap-2 mutants were largely indistinguishable from wild type. These findings indicate that several developmental roles of MIG-15 occur independently of RAP-2, suggesting that additional upstream regulators, including other small GTPases or adhesion-related pathways, control MIG-15 activity in specific developmental contexts.
","acknowledgements":"We thank members of the Reiner lab for helpful discussions. The mig-15(gk5002) CRISPR/Cas9 gene replacement was generously provided by M. Edgley and D. Moerman at the C. elegans Gene Knockout Facility at the University of British Columbia, which was funded by CIHR (Canada) and the NIH (USA). Some strains were provided by the Caenorhabditis Genetics Center, which is funded by the NIH Office of Research Infrastructure Programs (P40 OD010440). R.A.F. was supported in part by the Saudi Arabian Cultural Mission.
","authors":[{"affiliations":["Texas A&M University, Houston, TX, USA","Imam Abdulrahman bin Faisal University, Dammam 34212, Kingdom of Saudi Arabia"],"departments":["Vashisht College of Medicine","Clinical Laboratory Sciences Department, College of Applied Medical Sciences"],"credit":["investigation","methodology","formalAnalysis","visualization","conceptualization"],"email":"fakieh@tamu.edu","firstName":"Razan A.","lastName":"Fakieh","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":"","orcid":"0000-0002-3511-2665"},{"affiliations":["University of Pennsylvania, Philadelphia, PA, USA","California Institute of Technology, Pasadena, CA 91125, USA"],"departments":["Department of Genetics","Current address: Division of Biology and Biological Engineering"],"credit":["formalAnalysis","investigation","conceptualization","visualization"],"email":"ranjana@caltech.edu","firstName":"Ranjana","lastName":"Kishore","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"000-0002-1478-7671"},{"affiliations":["University of Pennsylvania, Philadelphia, PA, USA"],"departments":["Department of Genetics"],"credit":["conceptualization","fundingAcquisition","project","supervision","writing_reviewEditing","formalAnalysis","visualization"],"email":"sundaram@pennmedicine.upenn.edu","firstName":"Meera V.","lastName":"Sundaram","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"0000-0002-2940-8750"},{"affiliations":["Texas A&M University, Houston, TX USA","Texas A&M Health Science Center, Houston, TX, USA"],"departments":["Vashisht College of Medicine","Institute of Biosciences and Technology"],"credit":["conceptualization","formalAnalysis","fundingAcquisition","investigation","methodology","project","supervision","visualization","writing_originalDraft","writing_reviewEditing"],"email":"dreiner@tamu.edu","firstName":"David J.","lastName":"Reiner","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"0000-0002-0344-7161"}],"awards":[{"awardId":"R35 GM144237","funderName":"National Institutes of Health (United States)","awardRecipient":"David J. Reiner"},{"awardId":"R03 CA289854 ","funderName":"National Cancer Institute (United States)","awardRecipient":"David J. Reiner"},{"awardId":"R35 GM136315 ","funderName":"National Institutes of Health (United States)","awardRecipient":"Meera V. Sundaram"},{"awardId":"R01 GM058540","funderName":"National Institutes of Health (United States)","awardRecipient":"Meera V. Sundaram"}],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"","image":{"url":"https://portal.micropublication.org/uploads/cb1f537b0037af5a3f88beadda2e7011.png"},"imageCaption":"(A-C) Representative DIC photomicrographs of P6.px cells and the AC in mid-L3 animals used for assessing centering of the AC and the presumptive 1˚ lineage. Arrowheads indicate anchor cells (ACs) and brackets indicate P6.p daughters P6.pa and P6.px. (A) Wild type, (B) mig-15(rh148), and (C) rap-2(re400). (D-F) Schematics of P6.px centering on the AC for the same genotypes as A, B, C, respectively. (G-I) Representative DIC photomicrographs of vulval morphogenesis at the mid-L4 stage for the same genotypes as A, B, C, respectively. (J) Quantification of displacement of the midline between P6.pa and P6.pp from the midline of the AC reveals a strong defect in the mig-15 but not rap-2 mutants shown in A-F. (K) A radial locomotion assay of rap-2 vs. mig-15 mutants revealed severe locomotion defects in mig-15 mutants but none in rap-2 mutants. Distance shown is in mm from the origin at which animals were placed vs. final position after 20 minutes on 10 cm plates. N = 30 for each genotype. (L) DIC analysis of the wild type vs. rap-2 and mig-15 mutants for Vulvaless (Vul) and Abnormal (Abn) phenotypes (see Methods). ‡ These data were also presented in Fakieh and Reiner, 2025. ∞rhIs15 is a MIG-15::GFP over-expressing (OE) integrated transgene from Xiaoping Zhu and Edward Hedgecock (Zhu, 1998). §A small percentage (< 20%) of these animals showed multiple invaginations. F76% of these animals showed multiple invaginations. (M) Cell lineage analysis of P5.px, P6.px and P7.px cell divisions in vulval development during the late L3 stage. mig-15 mutants consistently show defects in the axes of this final cell division. The nomenclature used to describe the plane of cell divisions is L= longitudinal, T = transverse, O = oblique, N = no division. ANOVA was used for statistical analysis. **** represents p ≤ 0.0001, * represents p ≤ 0.05.
mig-15 mutants reveal vulval and locomotion defects not observed in rap-2 mutants
","methods":"Animal handling. All strains were derived from the N2 Bristol wild type. Animals were grown at 20 ˚C on OP50 E. coli seeded on NGM plates. Nomenclature was as described (Tuli, Daul, & Schedl, 2018). Wormbase and the Alliance of Genome Resources were both used (Sternberg et al., 2024).
The rap-2(gk11) knockout consortium deletion was backcrossed 5x to the wild type, rap-2(re400) is a STOP-IN disruption generated via CRISPR and rap-2(miz19dn) is a dominant negative mutation generated by CRISPR (Chen et al., 2018; Fakieh & Reiner, 2025). mig-15(rh148), mig-15(mu327) and mig-15(mu342) are kinase domain missense alleles, mig-15(gk5002) is a gene replacement, and mig-15(rh326) and mig-15(rh80) are nonsense alleles, all published previously (Fakieh & Reiner, 2025).
Imaging. Mid-L3, and mid-L4 animals were mounted on 3% agar pads containing 10 mM sodium azide as described (Sulston & Horvitz, 1977). Animals were scored using Differential Interference Contrast (DIC)/Nomarski optics on a Nikon Eclipse Ni microscope. Images were captured with an Andor Zyla camera and analyzed using Nikon NIS-Elements AR 4.20.00 software.
AC-VPC Centering assay. Animals were imaged using DIC microscopy at the Pn.px stage. Using the Nikon NIS Elements Advanced Research software, we measured the distance in microns between center of the AC nucleus and the mid-point between nuclei of the P6.pa and P6.pp daughter cells of P6.p.
VPC lineaging: The cell division planes of P5.pxx, P6.pxx and P7.pxx were observed by DIC/Nomarski microscopy. Nomenclature used to describe the polarity of cell divisions was L = longitudinal, T = transverse, O = oblique, and N = no division (Sternberg & Horvitz, 1986). By the L4 stage, vulval cell divisions and the invagination are normally complete. The numbers of vulval and non-vulval VPC descendants were counted to assess defects in cell-fate specification. Identities of individual nuclei were inferred based on their position and morphology and axes of final vulval divisions were determined by direct observation.
Radial locomotion assay. Locomotion was assayed as described (Mardick et al., 2021; Reiner, Newton, Tian, & Thomas, 1999; Reiner et al., 2006). Briefly, hermaphrodite adults without eggs were placed in the center of a 10-cm plate with a three-day evenly distributed lawn of OP50 E. coli and the origin was marked. Animals were allowed to move freely on the plate for 20 min at 20 ˚C. The plates were then transferred to -20 ˚C for 5 min to arrest movement. The final location of each animal was marked and the radial distance from the origin to the final point was measured to the nearest half mm. Statistical analysis was performed using Mann-Whitney U test and ANOVA (see figure legends for P values).
","reagents":"Strains used
All strains but NJ824 used for this study are described in (Fakieh & Reiner, 2025).
DV3054 rap-2(gk11) (5x backcrossed to N2)
DV3999 mig-15(gk5002 [gkIs267(mig-15::myo-2p>GFP::mig-15)]) (first-to-last-exon replacement)
","patternDescription":"MIG-15 is the sole Caenorhabditis elegans representative of the GCK-IV subfamily of Ste20 S/T kinases, which is conserved across metazoans. These proteins consist of an N-terminal Ste20 kinase domain, a long central proline-rich linker, and a C-terminal CNH domain (Citron-NIK Homology) (Chuang et al., 2016; Dan et al., 2001; Delpire, 2009). The Drosophila ortholog is Misshapen (Msn) and the mammalian orthologs are MAP4K4 (HGK/NIK), MAP4K6 (MINK1), and MAP4K7 (TNIK) (Bunardi et al., 2025). (NRK/NESK, sometimes referred to as MAP4K8, is generally not included in this group because its sequence is more divergent and expression is enriched in placenta (Denda et al., 2011), whereas the other GCK-IV kinases are broadly expressed.) The paralogous GCK-I subfamily of Ste20 kinases, consisting of C. elegans GCK-2, Drosophila Happyhour (Hppy) and mammalian MAP4K1,2,3,5, is structurally similar but functionally distinct.
MIG-15 in C. elegans regulates diverse morphogenetic and developmental processes (Chapman et al., 2008; Crawley et al., 2017; DaCunha et al., 2025; Huynh et al., 2026; Poinat et al., 2002; Shakir et al., 2006; Teuliere et al., 2011; Yang et al., 2014). Similar roles have been defined for Drosophila Msn (Kline et al., 2018; Paricio et al., 1999; Ruan et al., 2002; Su et al., 2000; Su et al., 1998).
The small GTPase Rap2 has been shown in mammalian systems and in vitro to bind or be phenotypically associated with MIG-15-like proteins of the GCK-IV subfamily. These findings indicate that, in mammals, GCK-IV Ste20 kinases can function as effectors of Rap2 (Gloerich et al., 2012; Hussain et al., 2010; Machida et al., 2004; Meng et al., 2018; Nonaka et al., 2008; Pannekoek et al., 2013; Taira et al., 2004). Recent studies make phenotypic connections between Drosophila Rap2l and Msn (Roberto et al., 2025), as well as between C. elegans RAP-2 and MIG-15 in synaptic tiling (Chen et al., 2018) and cell fate induction (Fakieh and Reiner, 2025).
During our studies, we observed that mig-15 mutant animals exhibit morphogenetic defects – in body shape, locomotion, and vulva – while rap-2 mutant animals are superficially wild type. Such a discrepancy is unexpected for a small GTPase and its effector, which often share loss-of-function phenotypes. Consequently, we characterized phenotypic defects in mig-15 relative to rap-2 mutant animals. These studies used putative mig-15 null mutations (gk5002, rh80, rh326) and missense mutations in conserved residues in the kinase domain (rh148, mu327, mu342), and putative rap-2 null mutations (gk11, re400) and a dominant-negative allele (miz19) (see Methods). Results were consistent across the multiple alleles tested.
Six ventral vulval precursor cells (VPCs), P3.p through P8.p, are spaced along the ventral midline during early larval development. Signal from the Anchor Cell (AC) induces these VPCs to assume the 3˚-3˚-2˚-1˚-2˚-3˚ pattern of VPC fates with 99.8% accuracy (Braendle and Felix, 2008; Shin et al., 2019). P6.p, closest to the AC, typically assumes the 1˚ fate, while the neighboring P5.p and P7.p cells assume the 2˚ fate (Shin and Reiner, 2018). During the L2 and early L3 stages, prior to its induction to assume the 1˚ fate, P6.p migrates to be positioned ventral to the AC (Grimbert et al., 2016). When assayed after the first VPC division, the P6.p daughters P6.pa and P6.pp were frequently displaced in mig-15(rh148) animals. In contrast, the P6.p daughters P6.pa and P6.pp in rap-2(re400) animals were positioned with the same accuracy as in wild type (Figure 1 A-C, schematized in Figure 1D-F and quantified in Figure 1J). The mid-L4 invaginated vulva, prior to eversion, forms a stereotyped structure that is frequently defective in mig-15(rh148) and other mig-15 mutants, but not a rap-2 mutant (Figure 1G-I; see also (Shin et al., 2018), quantified in Figure 1L. These defects included missing vulva cells (Vul phenotype) and, more frequently, mis-positioned vulva cells (Abn phenotype, Figure 1H). Overexpression of mig-15 (with transgene rhIs15, see Methods) caused similar vulva defects (Figure 1L). Analysis of VPC cell lineages by examining planes of cell division at the Pn.pxx cell division revealed defects in mig-15 mutants (Figure 1M).
By visual inspection, mig-15 mutant animals move poorly, while rap-2 mutants move normally. To assess general nervous system function via locomotion (Mardick et al., 2021), we measured radial locomotion of animals placed at the center of a plate. rap-2 mutants moved normally, while mig-15 mutants exhibited severe locomotion defects (Figure 1K). The putative null mig-15 mutations (gk5002, rh80, rh326) confer marginally more severe locomotion defects than the missense mutations (rh148, mu327, mu342).
Given the established relationships between Rap2 and MIG-15/GCK-IV orthologs, it is striking to observe loss-of-function mig-15 mutant phenotypes not phenocopied by loss-of-function mutations in rap-2. Consequently, we entertain the possibility that RAP-2 activates MIG-15 in only a subset of MIG-15 functions. Alternatively, RAP-2 could function redundantly with other inputs to control MIG-15 in selected tissues. MIG-15 mutant morphogenetic defects resemble those caused by mutations in MIG-2/RhoG and CED-10/Rac, as well as their activating RhoGEF UNC-73/TRIO (Kishore and Sundaram, 2002). This phenotypic similarity hints that these Rho family GTPases could activate MIG-15 in particular developmental contexts, in contrast to the Ras family GTPase Rap2.
By yeast two-hybrid assay, the CNH domain of MIG-15 interacts with the cytoplasmic domains of INA-1 ⍺ and PAT-3 β integrin subunits, predicted to form a laminin-binding integrin (Poinat et al., 2002). These interactions were supported by in vitro assays and experiments in HeLa and COS cells (Poinat et al., 2002). Genetic interactions in C. elegans are consistent with MIG-15 and INA-1/PAT-3 acting in the same pathway in axon guidance and fasciculation.
Mammalian TRAF1 (TNF receptor associated factor; (Inoue et al., 2000)) binds TNIK/MAP4K7 as an activator during inflammatory response (Fu et al., 1999), suggesting C. elegans TRAF orthologs TRF-1 and/or TRF-2 (Nikonorova et al., 2025) as potential upstream inputs. A negative regulator of GCK-IV MIG-15 subfamily proteins is the SH2-SH3 domain adaptor protein NCK, which binds to the central proline-rich region to sequester the kinase (Su et al., 1997). Release from this inhibition could activate MIG-15 in selected tissues.
Our results demonstrate that MIG-15 controls multiple morphogenetic and developmental processes in C. elegans that are not detectably dependent on RAP-2. These findings suggest that additional upstream regulators contribute to MIG-15 function in vivo, as well as in other systems where MIG-15-like GCK-IV subfamily proteins perform important functions.
","references":[{"reference":"Braendle C, Félix MA. 2008. Plasticity and errors of a robust developmental system in different environments. Dev Cell 15(5): 714-24.
","pubmedId":"19000836","doi":""},{"reference":"Bunardi CS, Yeom M, Kosasih P, Han H, Wang W, Seo G. 2025. MAP4K signaling pathways in cancer: roles, mechanisms and therapeutic opportunities. Exp Mol Med 57(10): 2148-2156.
","pubmedId":"41034525","doi":""},{"reference":"Chapman JO, Li H, Lundquist EA. 2008. The MIG-15 NIK kinase acts cell-autonomously in neuroblast polarization and migration in C. elegans. Dev Biol 324(2): 245-57.
","pubmedId":"18840424","doi":""},{"reference":"Chen X, Shibata AC, Hendi A, Kurashina M, Fortes E, Weilinger NL, et al., Mizumoto K. 2018. Rap2 and TNIK control Plexin-dependent tiled synaptic innervation in C. elegans. Elife 7: 10.7554/eLife.38801.
","pubmedId":"30063210","doi":""},{"reference":"Chuang HC, Wang X, Tan TH. 2016. MAP4K Family Kinases in Immunity and Inflammation. Advances in Immunology : 277-314.
","pubmedId":"","doi":" 10.1016/bs.ai.2015.09.006"},{"reference":"Crawley O, Giles AC, Desbois M, Kashyap S, Birnbaum R, Grill B. 2017. A MIG-15/JNK-1 MAP kinase cascade opposes RPM-1 signaling in synapse formation and learning. PLoS Genet 13(12): e1007095.
","pubmedId":"29228003","doi":""},{"reference":"DaCunha S, Silverman GA, Schedl T, Pak SC, Fielder SM, Penny GM. 2025. Null Mutant mig-15(udn323) Shows Touch Receptor Neuron Migration Defects in C. elegans. MicroPubl Biol 2025: 10.17912/micropub.biology.001904.
","pubmedId":"41426950","doi":""},{"reference":"Dan I, Watanabe NM, Kusumi A. 2001. The Ste20 group kinases as regulators of MAP kinase cascades. Trends Cell Biol 11(5): 220-30.
","pubmedId":"11316611","doi":""},{"reference":"Delpire E. 2009. The mammalian family of sterile 20p-like protein kinases. Pflugers Arch 458(5): 953-67.
","pubmedId":"19399514","doi":""},{"reference":"Denda K, Nakao-Wakabayashi K, Okamoto N, Kitamura N, Ryu JY, Tagawa YI, et al., Komada M. 2011. Nrk, an X-linked protein kinase in the germinal center kinase family, is required for placental development and fetoplacental induction of labor. J Biol Chem 286(33): 28802-28810.
","pubmedId":"21715335","doi":""},{"reference":"Fakieh RA, Reiner DJ. 2025. RAP-2 and CNH-MAP4 Kinase MIG-15 confer resistance in bystander epithelium to cell-fate transformation by excess Ras or Notch activity. Proc Natl Acad Sci U S A 122(1): e2414321121.
","pubmedId":"39739816","doi":""},{"reference":"Fu CA, Shen M, Huang BC, Lasaga J, Payan DG, Luo Y. 1999. TNIK, a novel member of the germinal center kinase family that activates the c-Jun N-terminal kinase pathway and regulates the cytoskeleton. J Biol Chem 274(43): 30729-37.
","pubmedId":"10521462","doi":""},{"reference":"Gloerich M, ten Klooster JP, Vliem MJ, Koorman T, Zwartkruis FJ, Clevers H, Bos JL. 2012. Rap2A links intestinal cell polarity to brush border formation. Nat Cell Biol 14(8): 793-801.
","pubmedId":"22797597","doi":""},{"reference":"Grimbert S, Tietze K, Barkoulas M, Sternberg PW, Félix MA, Braendle C. 2016. Anchor cell signaling and vulval precursor cell positioning establish a reproducible spatial context during C. elegans vulval induction. Dev Biol 416(1): 123-135.
","pubmedId":"27288708","doi":""},{"reference":"Hussain NK, Hsin H, Huganir RL, Sheng M. 2010. MINK and TNIK differentially act on Rap2-mediated signal transduction to regulate neuronal structure and AMPA receptor function. J Neurosci 30(44): 14786-94.
","pubmedId":"21048137","doi":""},{"reference":"Huynh L, Fakieh RA, Hendrix C, Powell R, Reiner DJ. 2026. Canonical and Non-canonical Hippo signaling in C. elegans. Genetics: pii: iyag056. 10.1093/genetics/iyag056.
","pubmedId":"41746831","doi":""},{"reference":"Inoue Ji, Ishida T, Tsukamoto N, Kobayashi N, Naito A, Azuma S, Yamamoto T. 2000. Tumor necrosis factor receptor-associated factor (TRAF) family: adapter proteins that mediate cytokine signaling. Exp Cell Res 254(1): 14-24.
","pubmedId":"10623461","doi":""},{"reference":"Kishore RS, Sundaram MV. 2002. ced-10 Rac and mig-2 function redundantly and act with unc-73 trio to control the orientation of vulval cell divisions and migrations in Caenorhabditis elegans. Dev Biol 241(2): 339-48.
","pubmedId":"11784116","doi":""},{"reference":"Kline A, Curry T, Lewellyn L. 2018. The Misshapen kinase regulates the size and stability of the germline ring canals in the Drosophila egg chamber. Dev Biol 440(2): 99-112.
","pubmedId":"29753016","doi":""},{"reference":"Machida N, Umikawa M, Takei K, Sakima N, Myagmar BE, Taira K, et al., Kariya K. 2004. Mitogen-activated protein kinase kinase kinase kinase 4 as a putative effector of Rap2 to activate the c-Jun N-terminal kinase. J Biol Chem 279(16): 15711-4.
","pubmedId":"14966141","doi":""},{"reference":"Mardick JI, Rasmussen NR, Wightman B, Reiner DJ. 2021. Parallel Rap1>RalGEF>Ral and Ras signals sculpt the C. elegans nervous system. Dev Biol 477: 37-48.
","pubmedId":"33991533","doi":""},{"reference":"Meng Z, Qiu Y, Lin KC, Kumar A, Placone JK, Fang C, et al., Guan KL. 2018. RAP2 mediates mechanoresponses of the Hippo pathway. Nature 560(7720): 655-660.
","pubmedId":"30135582","doi":""},{"reference":"Nikonorova IA, desRanleau E, Jacobs KC, Saul J, Walsh JD, Wang J, Barr MM. 2025. Polycystins recruit cargo to distinct ciliary extracellular vesicle subtypes in C. elegans. Nat Commun 16(1): 2899.
","pubmedId":"40180912","doi":""},{"reference":"Nonaka H, Takei K, Umikawa M, Oshiro M, Kuninaka K, Bayarjargal M, et al., Kariya KI. 2008. MINK is a Rap2 effector for phosphorylation of the postsynaptic scaffold protein TANC1. Biochem Biophys Res Commun 377(2): 573-578.
","pubmedId":"18930710","doi":""},{"reference":"Pannekoek WJ, Linnemann JR, Brouwer PM, Bos JL, Rehmann H. 2013. Rap1 and Rap2 antagonistically control endothelial barrier resistance. PLoS One 8(2): e57903.
","pubmedId":"23469100","doi":""},{"reference":"Paricio N, Feiguin F, Boutros M, Eaton S, Mlodzik M. 1999. The Drosophila STE20-like kinase misshapen is required downstream of the Frizzled receptor in planar polarity signaling. EMBO J 18(17): 4669-78.
","pubmedId":"10469646","doi":""},{"reference":"Poinat P, De Arcangelis A, Sookhareea S, Zhu X, Hedgecock EM, Labouesse M, Georges-Labouesse E. 2002. A conserved interaction between beta1 integrin/PAT-3 and Nck-interacting kinase/MIG-15 that mediates commissural axon navigation in C. elegans. Curr Biol 12(8): 622-31.
","pubmedId":"11967148","doi":""},{"reference":"Reiner DJ, Newton EM, Tian H, Thomas JH. 1999. Diverse behavioural defects caused by mutations in Caenorhabditis elegans unc-43 CaM kinase II. Nature 402(6758): 199-203.
","pubmedId":"10647014","doi":""},{"reference":"Reiner DJ, Weinshenker D, Tian H, Thomas JH, Nishiwaki K, Miwa J, et al., Garcia LR. 2006. Behavioral genetics of caenorhabditis elegans unc-103-encoded erg-like K(+) channel. J Neurogenet 20(1-2): 41-66.
","pubmedId":"16807195","doi":""},{"reference":"Roberto GM, Boutet A, Keil S, Del Guidice E, Duramé E, Tremblay MG, et al., Emery G. 2025. Tao and Rap2l ensure proper Misshapen activation and levels during Drosophila border cell migration. Dev Cell 60(1): 119-132.e6.
","pubmedId":"39393350","doi":""},{"reference":"Ruan W, Long H, Vuong DH, Rao Y. 2002. Bifocal is a downstream target of the Ste20-like serine/threonine kinase misshapen in regulating photoreceptor growth cone targeting in Drosophila. Neuron 36(5): 831-42.
","pubmedId":"12467587","doi":""},{"reference":"Shakir MA, Gill JS, Lundquist EA. 2006. Interactions of UNC-34 Enabled with Rac GTPases and the NIK kinase MIG-15 in Caenorhabditis elegans axon pathfinding and neuronal migration. Genetics 172(2): 893-913.
","pubmedId":"16204220","doi":""},{"reference":"Shin H, Braendle C, Monahan KB, Kaplan REW, Zand TP, Mote FS, Peters EC, Reiner DJ. 2019. Developmental fidelity is imposed by genetically separable RalGEF activities that mediate opposing signals. PLoS Genet 15(5): e1008056.
","pubmedId":"31086367","doi":""},{"reference":"Shin H, Kaplan REW, Duong T, Fakieh R, Reiner DJ. 2018. Ral Signals through a MAP4 Kinase-p38 MAP Kinase Cascade in C. elegans Cell Fate Patterning. Cell Rep 24(10): 2669-2681.e5.
","pubmedId":"30184501","doi":""},{"reference":"Shin H, Reiner DJ. 2018. The Signaling Network Controlling C. elegans Vulval Cell Fate Patterning. J Dev Biol 6(4): 10.3390/jdb6040030.
","pubmedId":"30544993","doi":""},{"reference":"Sternberg PW, Horvitz HR. 1986. Pattern formation during vulval development in C. elegans. Cell 44(5): 761-72.
","pubmedId":"3753901","doi":""},{"reference":"Sternberg PW, Van Auken K, Wang Q, Wright A, Yook K, Zarowiecki M, et al., Stein L. 2024. WormBase 2024: status and transitioning to Alliance infrastructure. Genetics 227(1): 10.1093/genetics/iyae050.
","pubmedId":"38573366","doi":""},{"reference":"Su YC, Han J, Xu S, Cobb M, Skolnik EY. 1997. NIK is a new Ste20-related kinase that binds NCK and MEKK1 and activates the SAPK/JNK cascade via a conserved regulatory domain. EMBO J 16(6): 1279-90.
","pubmedId":"9135144","doi":""},{"reference":"Su YC, Maurel-Zaffran C, Treisman JE, Skolnik EY. 2000. The Ste20 kinase misshapen regulates both photoreceptor axon targeting and dorsal closure, acting downstream of distinct signals. Mol Cell Biol 20(13): 4736-44.
","pubmedId":"10848599","doi":""},{"reference":"Su YC, Treisman JE, Skolnik EY. 1998. The Drosophila Ste20-related kinase misshapen is required for embryonic dorsal closure and acts through a JNK MAPK module on an evolutionarily conserved signaling pathway. Genes Dev 12(15): 2371-80.
","pubmedId":"9694801","doi":""},{"reference":"Sulston JE, Horvitz HR. 1977. Post-embryonic cell lineages of the nematode, Caenorhabditis elegans. Dev Biol 56(1): 110-56.
","pubmedId":"838129","doi":""},{"reference":"Taira K, Umikawa M, Takei K, Myagmar BE, Shinzato M, Machida N, et al., Kariya K. 2004. The Traf2- and Nck-interacting kinase as a putative effector of Rap2 to regulate actin cytoskeleton. J Biol Chem 279(47): 49488-96.
","pubmedId":"15342639","doi":""},{"reference":"Teulière J, Gally C, Garriga G, Labouesse M, Georges-Labouesse E. 2011. MIG-15 and ERM-1 promote growth cone directional migration in parallel to UNC-116 and WVE-1. Development 138(20): 4475-85.
","pubmedId":"21937599","doi":""},{"reference":"Tuli MA, Daul A, Schedl T. 2018. Caenorhabditis nomenclature. WormBook 2018: 1-14.
","pubmedId":"29722207","doi":""},{"reference":"Yang Y, Lee WS, Tang X, Wadsworth WG. 2014. Extracellular matrix regulates UNC-6 (netrin) axon guidance by controlling the direction of intracellular UNC-40 (DCC) outgrowth activity. PLoS One 9(5): e97258.
","pubmedId":"24824544","doi":""},{"reference":"Zhu, X. (1998). MIG-15, a NIK ortholog of the STE20 family of serine/threonine protein kinases, is involved in cell migration and cell signaling in C. elegans. [Dissertation]. [Baltimore (CA)]: John Hopkins University, 1989.
","pubmedId":"","doi":""}],"title":"RAP-2-independent roles for C. elegans MIG-15
","reviews":[],"curatorReviews":[{"curator":{"displayName":"KJ Yook"},"openAcknowledgement":false,"submitted":"1778804496211"}]},{"id":"db7da44e-e06b-4e95-b474-9e4c38dfd016","decision":"publish","abstract":"MIG-15 is the sole Caenorhabditis elegans member of the GCK-IV subfamily of Ste20 kinases. In mammals and in vitro, MIG-15-like kinases can function as effectors of the small GTPase Rap2. To test this model in vivo, we compared phenotypes of mig-15 and rap-2 mutants. mig-15 mutants displayed severe defects in vulval morphogenesis, cell positioning, and locomotion. In contrast, rap-2 mutants were largely indistinguishable from wild type. These findings indicate that several developmental roles of MIG-15 occur independently of RAP-2, suggesting that additional upstream regulators, including other small GTPases or adhesion-related pathways, control MIG-15 activity in specific developmental contexts.
","acknowledgements":"We thank members of the Reiner lab for helpful discussions. The mig-15(gk5002) CRISPR/Cas9 gene replacement was generously provided by M. Edgley and D. Moerman at the C. elegans Gene Knockout Facility at the University of British Columbia, which was funded by CIHR (Canada) and the NIH (USA). Some strains were provided by the Caenorhabditis Genetics Center, which is funded by the NIH Office of Research Infrastructure Programs (P40 OD010440). R.A.F. was supported in part by the Saudi Arabian Cultural Mission.
","authors":[{"affiliations":["Texas A&M University, Houston, TX USA","Imam Abdulrahman bin Faisal University, Dammam 34212, Kingdom of Saudi Arabia"],"departments":["Vashisht College of Medicine","Clinical Laboratory Sciences Department, College of Applied Medical Sciences"],"credit":["investigation","methodology","formalAnalysis","visualization","conceptualization"],"email":"fakieh@tamu.edu","firstName":"Razan A.","lastName":"Fakieh","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":"","orcid":"0000-0002-3511-2665"},{"affiliations":["University of Pennsylvania, Philadelphia, PA, USA","California Institute of Technology, Pasadena, CA 91125, USA"],"departments":["Department of Genetics","Current address: Division of Biology and Biological Engineering"],"credit":["formalAnalysis","investigation","conceptualization","visualization"],"email":"ranjana@caltech.edu","firstName":"Ranjana","lastName":"Kishore","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"000-0002-1478-7671"},{"affiliations":["University of Pennsylvania, Philadelphia, PA, USA"],"departments":["Department of Genetics"],"credit":["conceptualization","fundingAcquisition","project","supervision","writing_reviewEditing","formalAnalysis","visualization"],"email":"sundaram@pennmedicine.upenn.edu","firstName":"Meera V.","lastName":"Sundaram","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"0000-0002-2940-8750"},{"affiliations":["Texas A&M University, Houston, TX USA","Texas A&M Health Science Center, Houston, TX, USA"],"departments":["Vashisht College of Medicine","Institute of Biosciences and Technology"],"credit":["conceptualization","formalAnalysis","fundingAcquisition","investigation","methodology","project","supervision","visualization","writing_originalDraft","writing_reviewEditing"],"email":"dreiner@tamu.edu","firstName":"David J.","lastName":"Reiner","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"0000-0002-0344-7161"}],"awards":[{"awardId":"R35 GM144237","funderName":"National Institutes of Health (United States)","awardRecipient":"David J. Reiner"},{"awardId":"R03 CA289854 ","funderName":"National Cancer Institute (United States)","awardRecipient":"David J. Reiner"},{"awardId":"R35 GM136315 ","funderName":"National Institutes of Health (United States)","awardRecipient":"Meera V. Sundaram"},{"awardId":"R01 GM058540","funderName":"National Institutes of Health (United States)","awardRecipient":"Meera V. Sundaram"}],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"","image":{"url":"https://portal.micropublication.org/uploads/cb1f537b0037af5a3f88beadda2e7011.png"},"imageCaption":"(A-C) Representative DIC photomicrographs of P6.px cells and the AC in mid-L3 animals used for assessing centering of the AC and the presumptive 1˚ lineage. Arrowheads indicate anchor cells (ACs) and brackets indicate P6.p daughters P6.pa and P6.px. (A) Wild type, (B) mig-15(rh148), and (C) rap-2(re400). (D-F) Schematics of P6.px centering on the AC for the same genotypes as A, B, C, respectively. (G-I) Representative DIC photomicrographs of vulval morphogenesis at the mid-L4 stage for the same genotypes as A, B, C, respectively. (J) Quantification of displacement of the midline between P6.pa and P6.pp from the midline of the AC reveals a strong defect in the mig-15 but not rap-2 mutants shown in A-F. (K) A radial locomotion assay of rap-2 vs. mig-15 mutants revealed severe locomotion defects in mig-15 mutants but none in rap-2 mutants. Distance shown is in mm from the origin at which animals were placed vs. final position after 20 minutes on 10 cm plates. N = 30 for each genotype. (L) DIC analysis of the wild type vs. rap-2 and mig-15 mutants for Vulvaless (Vul) and Abnormal (Abn) phenotypes (see Methods). ‡ These data were also presented in Fakieh and Reiner, 2025. ∞rhIs15 is a MIG-15::GFP over-expressing (OE) integrated transgene from Xiaoping Zhu and Edward Hedgecock (Zhu, 1998). §A small percentage (< 20%) of these animals showed multiple invaginations. Φ76% of these animals showed multiple invaginations. (M) Cell lineage analysis of P5.px, P6.px and P7.px cell divisions in vulval development during the late L3 stage. mig-15 mutants consistently show defects in the axes of this final cell division. The nomenclature used to describe the plane of cell divisions is L= longitudinal, T = transverse, O = oblique, N = no division. ANOVA was used for statistical analysis. **** represents p ≤ 0.0001, * represents p ≤ 0.05.
","imageTitle":"mig-15 mutants reveal vulval and locomotion defects not observed in rap-2 mutants
","methods":"Animal handling. All strains were derived from the N2 Bristol wild type. Animals were grown at 20 ˚C on OP50 E. coli seeded on NGM plates. Nomenclature was as described (Tuli, Daul, & Schedl, 2018). Wormbase and the Alliance of Genome Resources were both used (Sternberg et al., 2024).
The rap-2(gk11) knockout consortium deletion was backcrossed 5x to the wild type, rap-2(re400) is a STOP-IN disruption generated via CRISPR and rap-2(miz19dn) is a dominant negative mutation generated by CRISPR (Chen et al., 2018; Fakieh & Reiner, 2025). mig-15(rh148), mig-15(mu327) and mig-15(mu342) are kinase domain missense alleles, mig-15(gk5002) is a gene replacement, and mig-15(rh326) and mig-15(rh80) are nonsense alleles, all published previously (Fakieh & Reiner, 2025).
Imaging. Mid-L3, and mid-L4 animals were mounted on 3% agar pads containing 10 mM sodium azide as described (Sulston & Horvitz, 1977). Animals were scored using Differential Interference Contrast (DIC)/Nomarski optics on a Nikon Eclipse Ni microscope. Images were captured with an Andor Zyla camera and analyzed using Nikon NIS-Elements AR 4.20.00 software.
AC-VPC Centering assay. Animals were imaged using DIC microscopy at the Pn.px stage. Using the Nikon NIS Elements Advanced Research software, we measured the distance in microns between center of the AC nucleus and the mid-point between nuclei of the P6.pa and P6.pp daughter cells of P6.p.
VPC lineaging: The cell division planes of P5.pxx, P6.pxx and P7.pxx were observed by DIC/Nomarski microscopy. Nomenclature used to describe the polarity of cell divisions was L = longitudinal, T = transverse, O = oblique, and N = no division (Sternberg & Horvitz, 1986). By the L4 stage, vulval cell divisions and the invagination are normally complete. The numbers of vulval and non-vulval VPC descendants were counted to assess defects in cell-fate specification. Identities of individual nuclei were inferred based on their position and morphology and axes of final vulval divisions were determined by direct observation.
Radial locomotion assay. Locomotion was assayed as described (Mardick et al., 2021; Reiner, Newton, Tian, & Thomas, 1999; Reiner et al., 2006). Briefly, hermaphrodite adults without eggs were placed in the center of a 10-cm plate with a three-day evenly distributed lawn of OP50 E. coli and the origin was marked. Animals were allowed to move freely on the plate for 20 min at 20 ˚C. The plates were then transferred to -20 ˚C for 5 min to arrest movement. The final location of each animal was marked and the radial distance from the origin to the final point was measured to the nearest half mm. Statistical analysis was performed using Mann-Whitney U test and ANOVA (see figure legends for P values).
","reagents":"Strains used
All strains but NJ824 used for this study are described in (Fakieh & Reiner, 2025).
DV3054 rap-2(gk11) (5x backcrossed to N2)
DV3999 mig-15(gk5002 [gkIs267(mig-15::myo-2p>GFP::mig-15)]) (first-to-last-exon replacement)
","patternDescription":"MIG-15 is the sole Caenorhabditis elegans representative of the GCK-IV subfamily of Ste20 S/T kinases, which is conserved across metazoans. These proteins consist of an N-terminal Ste20 kinase domain, a long central proline-rich linker, and a C-terminal CNH domain (Citron-NIK Homology) (Chuang et al., 2016; Dan et al., 2001; Delpire, 2009). The Drosophila ortholog is Misshapen (Msn) and the mammalian orthologs are MAP4K4 (HGK/NIK), MAP4K6 (MINK1), and MAP4K7 (TNIK) (Bunardi et al., 2025). (NRK/NESK, sometimes referred to as MAP4K8, is generally not included in this group because its sequence is more divergent and expression is enriched in placenta (Denda et al., 2011), whereas the other GCK-IV kinases are broadly expressed.) The paralogous GCK-I subfamily of Ste20 kinases, consisting of C. elegans GCK-2, Drosophila Happyhour (Hppy) and mammalian MAP4K1,2,3,5, is structurally similar but functionally distinct.
MIG-15 in C. elegans regulates diverse morphogenetic and developmental processes (Chapman et al., 2008; Crawley et al., 2017; DaCunha et al., 2025; Huynh et al., 2026; Poinat et al., 2002; Shakir et al., 2006; Teuliere et al., 2011; Yang et al., 2014). Similar roles have been defined for Drosophila Msn (Kline et al., 2018; Paricio et al., 1999; Ruan et al., 2002; Su et al., 2000; Su et al., 1998).
The small GTPase Rap2 has been shown in mammalian systems and in vitro to bind or be phenotypically associated with MIG-15-like proteins of the GCK-IV subfamily. These findings indicate that, in mammals, GCK-IV Ste20 kinases can function as effectors of Rap2 (Gloerich et al., 2012; Hussain et al., 2010; Machida et al., 2004; Meng et al., 2018; Nonaka et al., 2008; Pannekoek et al., 2013; Taira et al., 2004). Recent studies make phenotypic connections between Drosophila Rap2l and Msn (Roberto et al., 2025), as well as between C. elegans RAP-2 and MIG-15 in synaptic tiling (Chen et al., 2018) and cell fate induction (Fakieh and Reiner, 2025).
During our studies, we observed that mig-15 mutant animals exhibit morphogenetic defects – in body shape, locomotion, and vulva – while rap-2 mutant animals are superficially wild type. Such a discrepancy is unexpected for a small GTPase and its effector, which often share loss-of-function phenotypes. Consequently, we characterized phenotypic defects in mig-15 relative to rap-2 mutant animals. These studies used putative mig-15 null mutations (gk5002, rh80, rh326) and missense mutations in conserved residues in the kinase domain (rh148, mu327, mu342), and putative rap-2 null mutations (gk11, re400) and a dominant-negative allele (miz19) (see Methods). Results were consistent across the multiple alleles tested.
Six ventral vulval precursor cells (VPCs), P3.p through P8.p, are spaced along the ventral midline during early larval development. Signal from the Anchor Cell (AC) induces these VPCs to assume the 3˚-3˚-2˚-1˚-2˚-3˚ pattern of VPC fates with 99.8% accuracy (Braendle and Felix, 2008; Shin et al., 2019). P6.p, closest to the AC, typically assumes the 1˚ fate, while the neighboring P5.p and P7.p cells assume the 2˚ fate (Shin and Reiner, 2018). During the L2 and early L3 stages, prior to its induction to assume the 1˚ fate, P6.p migrates to be positioned ventral to the AC (Grimbert et al., 2016). When assayed after the first VPC division, the P6.p daughters P6.pa and P6.pp were frequently displaced in mig-15(rh148) animals. In contrast, the P6.p daughters P6.pa and P6.pp in rap-2(re400) animals were positioned with the same accuracy as in wild type (Figure 1 A-C, schematized in Figure 1D-F and quantified in Figure 1J). The mid-L4 invaginated vulva, prior to eversion, forms a stereotyped structure that is frequently defective in mig-15(rh148) and other mig-15 mutants, but not a rap-2 mutant (Figure 1G-I; see also (Shin et al., 2018), quantified in Figure 1L. These defects included missing vulva cells (Vul phenotype) and, more frequently, mis-positioned vulva cells (Abn phenotype, Figure 1H). Overexpression of mig-15 (with transgene rhIs15, see Methods) caused similar vulva defects (Figure 1L). Analysis of VPC cell lineages by examining planes of cell division at the Pn.pxx cell division revealed defects in mig-15 mutants (Figure 1M).
By visual inspection, mig-15 mutant animals move poorly, while rap-2 mutants move normally. To assess general nervous system function via locomotion (Mardick et al., 2021), we measured radial locomotion of animals placed at the center of a plate. rap-2 mutants moved normally, while mig-15 mutants exhibited severe locomotion defects (Figure 1K). The putative null mig-15 mutations (gk5002, rh80, rh326) confer marginally more severe locomotion defects than the missense mutations (rh148, mu327, mu342).
Given the established relationships between Rap2 and MIG-15/GCK-IV orthologs, it is striking to observe loss-of-function mig-15 mutant phenotypes not phenocopied by loss-of-function mutations in rap-2. Consequently, we entertain the possibility that RAP-2 activates MIG-15 in only a subset of MIG-15 functions. Alternatively, RAP-2 could function redundantly with other inputs to control MIG-15 in selected tissues. MIG-15 mutant morphogenetic defects resemble those caused by mutations in MIG-2/RhoG and CED-10/Rac, as well as their activating RhoGEF UNC-73/TRIO (Kishore and Sundaram, 2002). This phenotypic similarity hints that these Rho family GTPases could activate MIG-15 in particular developmental contexts, in contrast to the Ras family GTPase Rap2.
By yeast two-hybrid assay, the CNH domain of MIG-15 interacts with the cytoplasmic domains of INA-1 ⍺ and PAT-3 β integrin subunits, predicted to form a laminin-binding integrin (Poinat et al., 2002). These interactions were supported by in vitro assays and experiments in HeLa and COS cells (Poinat et al., 2002). Genetic interactions in C. elegans are consistent with MIG-15 and INA-1/PAT-3 acting in the same pathway in axon guidance and fasciculation.
Mammalian TRAF1 (TNF receptor associated factor; (Inoue et al., 2000)) binds TNIK/MAP4K7 as an activator during inflammatory response (Fu et al., 1999), suggesting C. elegans TRAF orthologs TRF-1 and/or TRF-2 (Nikonorova et al., 2025) as potential upstream inputs. A negative regulator of GCK-IV MIG-15 subfamily proteins is the SH2-SH3 domain adaptor protein NCK, which binds to the central proline-rich region to sequester the kinase (Su et al., 1997). Release from this inhibition could activate MIG-15 in selected tissues.
Our results demonstrate that MIG-15 controls multiple morphogenetic and developmental processes in C. elegans that are not detectably dependent on RAP-2. These findings suggest that additional upstream regulators contribute to MIG-15 function in vivo, as well as in other systems where MIG-15-like GCK-IV subfamily proteins perform important functions.
","references":[{"reference":"Braendle C, Félix MA. 2008. Plasticity and errors of a robust developmental system in different environments. Dev Cell 15(5): 714-24.
","pubmedId":"19000836","doi":""},{"reference":"Bunardi CS, Yeom M, Kosasih P, Han H, Wang W, Seo G. 2025. MAP4K signaling pathways in cancer: roles, mechanisms and therapeutic opportunities. Exp Mol Med 57(10): 2148-2156.
","pubmedId":"41034525","doi":""},{"reference":"Chapman JO, Li H, Lundquist EA. 2008. The MIG-15 NIK kinase acts cell-autonomously in neuroblast polarization and migration in C. elegans. Dev Biol 324(2): 245-57.
","pubmedId":"18840424","doi":""},{"reference":"Chen X, Shibata AC, Hendi A, Kurashina M, Fortes E, Weilinger NL, et al., Mizumoto K. 2018. Rap2 and TNIK control Plexin-dependent tiled synaptic innervation in C. elegans. Elife 7: 10.7554/eLife.38801.
","pubmedId":"30063210","doi":""},{"reference":"Chuang HC, Wang X, Tan TH. 2016. MAP4K Family Kinases in Immunity and Inflammation. Advances in Immunology : 277-314.
","pubmedId":"","doi":" 10.1016/bs.ai.2015.09.006"},{"reference":"Crawley O, Giles AC, Desbois M, Kashyap S, Birnbaum R, Grill B. 2017. A MIG-15/JNK-1 MAP kinase cascade opposes RPM-1 signaling in synapse formation and learning. PLoS Genet 13(12): e1007095.
","pubmedId":"29228003","doi":""},{"reference":"DaCunha S, Silverman GA, Schedl T, Pak SC, Fielder SM, Penny GM. 2025. Null Mutant mig-15(udn323) Shows Touch Receptor Neuron Migration Defects in C. elegans. MicroPubl Biol 2025: 10.17912/micropub.biology.001904.
","pubmedId":"41426950","doi":""},{"reference":"Dan I, Watanabe NM, Kusumi A. 2001. The Ste20 group kinases as regulators of MAP kinase cascades. Trends Cell Biol 11(5): 220-30.
","pubmedId":"11316611","doi":""},{"reference":"Delpire E. 2009. The mammalian family of sterile 20p-like protein kinases. Pflugers Arch 458(5): 953-67.
","pubmedId":"19399514","doi":""},{"reference":"Denda K, Nakao-Wakabayashi K, Okamoto N, Kitamura N, Ryu JY, Tagawa YI, et al., Komada M. 2011. Nrk, an X-linked protein kinase in the germinal center kinase family, is required for placental development and fetoplacental induction of labor. J Biol Chem 286(33): 28802-28810.
","pubmedId":"21715335","doi":""},{"reference":"Fakieh RA, Reiner DJ. 2025. RAP-2 and CNH-MAP4 Kinase MIG-15 confer resistance in bystander epithelium to cell-fate transformation by excess Ras or Notch activity. Proc Natl Acad Sci U S A 122(1): e2414321121.
","pubmedId":"39739816","doi":""},{"reference":"Fu CA, Shen M, Huang BC, Lasaga J, Payan DG, Luo Y. 1999. TNIK, a novel member of the germinal center kinase family that activates the c-Jun N-terminal kinase pathway and regulates the cytoskeleton. J Biol Chem 274(43): 30729-37.
","pubmedId":"10521462","doi":""},{"reference":"Gloerich M, ten Klooster JP, Vliem MJ, Koorman T, Zwartkruis FJ, Clevers H, Bos JL. 2012. Rap2A links intestinal cell polarity to brush border formation. Nat Cell Biol 14(8): 793-801.
","pubmedId":"22797597","doi":""},{"reference":"Grimbert S, Tietze K, Barkoulas M, Sternberg PW, Félix MA, Braendle C. 2016. Anchor cell signaling and vulval precursor cell positioning establish a reproducible spatial context during C. elegans vulval induction. Dev Biol 416(1): 123-135.
","pubmedId":"27288708","doi":""},{"reference":"Hussain NK, Hsin H, Huganir RL, Sheng M. 2010. MINK and TNIK differentially act on Rap2-mediated signal transduction to regulate neuronal structure and AMPA receptor function. J Neurosci 30(44): 14786-94.
","pubmedId":"21048137","doi":""},{"reference":"Huynh L, Fakieh RA, Hendrix C, Powell R, Reiner DJ. 2026. Canonical and Non-canonical Hippo signaling in C. elegans. Genetics: pii: iyag056. 10.1093/genetics/iyag056.
","pubmedId":"41746831","doi":""},{"reference":"Inoue Ji, Ishida T, Tsukamoto N, Kobayashi N, Naito A, Azuma S, Yamamoto T. 2000. Tumor necrosis factor receptor-associated factor (TRAF) family: adapter proteins that mediate cytokine signaling. Exp Cell Res 254(1): 14-24.
","pubmedId":"10623461","doi":""},{"reference":"Kishore RS, Sundaram MV. 2002. ced-10 Rac and mig-2 function redundantly and act with unc-73 trio to control the orientation of vulval cell divisions and migrations in Caenorhabditis elegans. Dev Biol 241(2): 339-48.
","pubmedId":"11784116","doi":""},{"reference":"Kline A, Curry T, Lewellyn L. 2018. The Misshapen kinase regulates the size and stability of the germline ring canals in the Drosophila egg chamber. Dev Biol 440(2): 99-112.
","pubmedId":"29753016","doi":""},{"reference":"Machida N, Umikawa M, Takei K, Sakima N, Myagmar BE, Taira K, et al., Kariya K. 2004. Mitogen-activated protein kinase kinase kinase kinase 4 as a putative effector of Rap2 to activate the c-Jun N-terminal kinase. J Biol Chem 279(16): 15711-4.
","pubmedId":"14966141","doi":""},{"reference":"Mardick JI, Rasmussen NR, Wightman B, Reiner DJ. 2021. Parallel Rap1>RalGEF>Ral and Ras signals sculpt the C. elegans nervous system. Dev Biol 477: 37-48.
","pubmedId":"33991533","doi":""},{"reference":"Meng Z, Qiu Y, Lin KC, Kumar A, Placone JK, Fang C, et al., Guan KL. 2018. RAP2 mediates mechanoresponses of the Hippo pathway. Nature 560(7720): 655-660.
","pubmedId":"30135582","doi":""},{"reference":"Nikonorova IA, desRanleau E, Jacobs KC, Saul J, Walsh JD, Wang J, Barr MM. 2025. Polycystins recruit cargo to distinct ciliary extracellular vesicle subtypes in C. elegans. Nat Commun 16(1): 2899.
","pubmedId":"40180912","doi":""},{"reference":"Nonaka H, Takei K, Umikawa M, Oshiro M, Kuninaka K, Bayarjargal M, et al., Kariya KI. 2008. MINK is a Rap2 effector for phosphorylation of the postsynaptic scaffold protein TANC1. Biochem Biophys Res Commun 377(2): 573-578.
","pubmedId":"18930710","doi":""},{"reference":"Pannekoek WJ, Linnemann JR, Brouwer PM, Bos JL, Rehmann H. 2013. Rap1 and Rap2 antagonistically control endothelial barrier resistance. PLoS One 8(2): e57903.
","pubmedId":"23469100","doi":""},{"reference":"Paricio N, Feiguin F, Boutros M, Eaton S, Mlodzik M. 1999. The Drosophila STE20-like kinase misshapen is required downstream of the Frizzled receptor in planar polarity signaling. EMBO J 18(17): 4669-78.
","pubmedId":"10469646","doi":""},{"reference":"Poinat P, De Arcangelis A, Sookhareea S, Zhu X, Hedgecock EM, Labouesse M, Georges-Labouesse E. 2002. A conserved interaction between beta1 integrin/PAT-3 and Nck-interacting kinase/MIG-15 that mediates commissural axon navigation in C. elegans. Curr Biol 12(8): 622-31.
","pubmedId":"11967148","doi":""},{"reference":"Reiner DJ, Newton EM, Tian H, Thomas JH. 1999. Diverse behavioural defects caused by mutations in Caenorhabditis elegans unc-43 CaM kinase II. Nature 402(6758): 199-203.
","pubmedId":"10647014","doi":""},{"reference":"Reiner DJ, Weinshenker D, Tian H, Thomas JH, Nishiwaki K, Miwa J, et al., Garcia LR. 2006. Behavioral genetics of caenorhabditis elegans unc-103-encoded erg-like K(+) channel. J Neurogenet 20(1-2): 41-66.
","pubmedId":"16807195","doi":""},{"reference":"Roberto GM, Boutet A, Keil S, Del Guidice E, Duramé E, Tremblay MG, et al., Emery G. 2025. Tao and Rap2l ensure proper Misshapen activation and levels during Drosophila border cell migration. Dev Cell 60(1): 119-132.e6.
","pubmedId":"39393350","doi":""},{"reference":"Ruan W, Long H, Vuong DH, Rao Y. 2002. Bifocal is a downstream target of the Ste20-like serine/threonine kinase misshapen in regulating photoreceptor growth cone targeting in Drosophila. Neuron 36(5): 831-42.
","pubmedId":"12467587","doi":""},{"reference":"Shakir MA, Gill JS, Lundquist EA. 2006. Interactions of UNC-34 Enabled with Rac GTPases and the NIK kinase MIG-15 in Caenorhabditis elegans axon pathfinding and neuronal migration. Genetics 172(2): 893-913.
","pubmedId":"16204220","doi":""},{"reference":"Shin H, Braendle C, Monahan KB, Kaplan REW, Zand TP, Mote FS, Peters EC, Reiner DJ. 2019. Developmental fidelity is imposed by genetically separable RalGEF activities that mediate opposing signals. PLoS Genet 15(5): e1008056.
","pubmedId":"31086367","doi":""},{"reference":"Shin H, Kaplan REW, Duong T, Fakieh R, Reiner DJ. 2018. Ral Signals through a MAP4 Kinase-p38 MAP Kinase Cascade in C. elegans Cell Fate Patterning. Cell Rep 24(10): 2669-2681.e5.
","pubmedId":"30184501","doi":""},{"reference":"Shin H, Reiner DJ. 2018. The Signaling Network Controlling C. elegans Vulval Cell Fate Patterning. J Dev Biol 6(4): 10.3390/jdb6040030.
","pubmedId":"30544993","doi":""},{"reference":"Sternberg PW, Horvitz HR. 1986. Pattern formation during vulval development in C. elegans. Cell 44(5): 761-72.
","pubmedId":"3753901","doi":""},{"reference":"Sternberg PW, Van Auken K, Wang Q, Wright A, Yook K, Zarowiecki M, et al., Stein L. 2024. WormBase 2024: status and transitioning to Alliance infrastructure. Genetics 227(1): 10.1093/genetics/iyae050.
","pubmedId":"38573366","doi":""},{"reference":"Su YC, Han J, Xu S, Cobb M, Skolnik EY. 1997. NIK is a new Ste20-related kinase that binds NCK and MEKK1 and activates the SAPK/JNK cascade via a conserved regulatory domain. EMBO J 16(6): 1279-90.
","pubmedId":"9135144","doi":""},{"reference":"Su YC, Maurel-Zaffran C, Treisman JE, Skolnik EY. 2000. The Ste20 kinase misshapen regulates both photoreceptor axon targeting and dorsal closure, acting downstream of distinct signals. Mol Cell Biol 20(13): 4736-44.
","pubmedId":"10848599","doi":""},{"reference":"Su YC, Treisman JE, Skolnik EY. 1998. The Drosophila Ste20-related kinase misshapen is required for embryonic dorsal closure and acts through a JNK MAPK module on an evolutionarily conserved signaling pathway. Genes Dev 12(15): 2371-80.
","pubmedId":"9694801","doi":""},{"reference":"Sulston JE, Horvitz HR. 1977. Post-embryonic cell lineages of the nematode, Caenorhabditis elegans. Dev Biol 56(1): 110-56.
","pubmedId":"838129","doi":""},{"reference":"Taira K, Umikawa M, Takei K, Myagmar BE, Shinzato M, Machida N, et al., Kariya K. 2004. The Traf2- and Nck-interacting kinase as a putative effector of Rap2 to regulate actin cytoskeleton. J Biol Chem 279(47): 49488-96.
","pubmedId":"15342639","doi":""},{"reference":"Teulière J, Gally C, Garriga G, Labouesse M, Georges-Labouesse E. 2011. MIG-15 and ERM-1 promote growth cone directional migration in parallel to UNC-116 and WVE-1. Development 138(20): 4475-85.
","pubmedId":"21937599","doi":""},{"reference":"Tuli MA, Daul A, Schedl T. 2018. Caenorhabditis nomenclature. WormBook 2018: 1-14.
","pubmedId":"29722207","doi":""},{"reference":"Yang Y, Lee WS, Tang X, Wadsworth WG. 2014. Extracellular matrix regulates UNC-6 (netrin) axon guidance by controlling the direction of intracellular UNC-40 (DCC) outgrowth activity. PLoS One 9(5): e97258.
","pubmedId":"24824544","doi":""},{"reference":"Zhu, X. (1998). MIG-15, a NIK ortholog of the STE20 family of serine/threonine protein kinases, is involved in cell migration and cell signaling in C. elegans. [Dissertation]. [Baltimore (CA)]: John Hopkins University, 1989.
","pubmedId":"","doi":""}],"title":"RAP-2-independent roles for C. elegans MIG-15
","reviews":[],"curatorReviews":[{"curator":{"displayName":"KJ Yook"},"openAcknowledgement":false,"submitted":null}]}]}},"species":{"species":[{"value":"acer saccharum","label":"Acer saccharum","imageSrc":"","imageAlt":"","mod":"TreeGenes","modLink":"https://treegenesdb.org","linkVariable":""},{"value":"achillea millefolium","label":"Achillea millefolium","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"acinetobacter baylyi","label":"Acinetobacter baylyi","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"actinobacteria bacterium","label":"Actinobacteria bacterium","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"adelges tsugae","label":"Adelges tsugae","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"adenocaulon chilense","label":"Adenocaulon chilense","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"aedes japonicus","label":"Aedes japonicus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"aegorhinus vitulus","label":"Aegorhinus vitulus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"alaimidae","label":"Alaimidae","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"allobates femoralis","label":"Allobates femoralis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"alnus glutinosa","label":"Alnus glutinosa","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"alosa aestivalis","label":"Alosa aestivalis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"alosa pseudoharengus","label":"Alosa pseudoharengus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"alternaria alternata","label":"Alternaria alternata","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"amynthas agrestis","label":"Amynthas Agrestis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ancylostoma caninum","label":"Ancylostoma caninum","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ancylostoma ceylanicum","label":"Ancylostoma ceylanicum","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"anemone multifida","label":"Anemone multifida","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"anguilla rostrata","label":"Anguilla rostrata","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"anisakis simplex","label":"Anisakis simplex","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"anomala albopilosa","label":"Anomala albopilosa","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"anthomyiidae sp","label":"Anthomyiidae sp","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"anthomyiidae sp","label":"Anthomyiidae sp","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"arabidopsis","label":"Arabidopsis","imageSrc":"arabidopsis.png","imageAlt":"Arabidopsis graphic by Zoe Zorn CC BY 4.0","mod":"TAIR","modLink":"https://arabidopsis.org","linkVariable":""},{"value":"architeuthis dux","label":"Architeuthis dux","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"arion vulgaris","label":"Arion vulgaris","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"armeria","label":"Armeria","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"artemia","label":"Artemia","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"arthrobacter sp.","label":"Arthrobacter sp.","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ascaridia","label":"Ascaridia","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ascaridia galli","label":"Ascaridia galli","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"asparagopsis taxiformis","label":"Asparagopsis taxiformis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"astatotilapia burtoni","label":"Astatotilapia burtoni","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"avena sativa","label":"Avena sativa","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"aves","label":"Aves","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"bacillus","label":"Bacillus (firmicutes)","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"bacillus cereus","label":"Bacillus cereus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"bacillus mycoides","label":"Bacillus mycoides","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"bacillus subtilis","label":"Bacillus subtilis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"bacillus thuringiensis","label":"Bacillus thuringiensis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"bacillus toyonensis","label":"Bacillus toyonensis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"bacillus wiedmannii","label":"Bacillus wiedmannii","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"bacteria","label":"Bacteria","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"bacteriophage","label":"Bacteriophage","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"bactrocera","label":"Bactrocera sp.","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"batrachospermum gelatinosum","label":"Batrachospermum gelatinosum","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"betula lenta","label":"Betula lenta","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"betula nigra","label":"Betula nigra","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"bombus dahlbohmii","label":"Bombus dahlbohmii","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"bombus terrestris","label":"Bombus terrestris","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"bombyx mori","label":"Bombyx mori","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"bos taurus","label":"Bos Taurus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"brachygobius doriae","label":"Brachygobius doriae","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"brassica oleracea","label":"Brassica oleracea","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"brassica rapa","label":"Brassica rapa","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"brugia malayi","label":"Brugia malayi","imageSrc":"","imageAlt":"","mod":"WormBase","modLink":"www.wormbase.org","linkVariable":""},{"value":"burkholderia thailandensis","label":"Burkholderia thailandensis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"buttiauxella","label":"Buttiauxella","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"caenorhabditis brenneri","label":"Caenorhabditis brenneri","imageSrc":"","imageAlt":"","mod":"WormBase","modLink":"www.wormbase.org","linkVariable":""},{"value":"caenorhabditis briggsae","label":"Caenorhabditis briggsae","imageSrc":"","imageAlt":"","mod":"WormBase","modLink":"www.wormbase.org","linkVariable":""},{"value":"c. elegans","label":"Caenorhabditis elegans","imageSrc":"c-elegans.jpg","imageAlt":"C. elegans graphic by Zoe Zorn CC BY 4.0","mod":"WormBase","modLink":"https://wormbase.org","linkVariable":""},{"value":"caenorhabditis inopinata","label":"Caenorhabditis inopinata","imageSrc":"","imageAlt":"","mod":"WormBase","modLink":"www.wormbase.org","linkVariable":""},{"value":"caenorhabditis japonica","label":"Caenorhabditis japonica","imageSrc":"","imageAlt":"","mod":"WormBase","modLink":"www.wormbase.org","linkVariable":""},{"value":"caenorhabditis nigoni","label":"Caenorhabditis nigoni","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"caenorhabditis remanei","label":"Caenorhabditis remanei","imageSrc":"","imageAlt":"","mod":"WormBase","modLink":"www.wormbase.org","linkVariable":""},{"value":"caenorhabditis tropicalis","label":"Caenorhabditis tropicalis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"calidifontibacillus","label":"Calidifontibacillus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"calidifontibacillus erzuremensis","label":"Calidifontibacillus erzuremensis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"calliphora sp","label":"Calliphora sp","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"caltha sagittata","label":"Caltha sagittata","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"cambarus latimanus","label":"Cambarus latimanus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"candida albicans","label":"Candida albicans","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"canis familiaris","label":"Canis familiaris","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"cannabis sativa","label":"Cannabis sativa","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"caretta caretta","label":"Caretta caretta","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"cassiopea xamachana","label":"Cassiopea xamachana","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"caulobacter vibrioides","label":"Caulobacter vibrioides","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"cephalopods","label":"Cephalopoda","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"cerastium arvense","label":"Cerastium arvense","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ceriodaphnia","label":"Ceriodaphnia","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ceroglossus suturalis","label":"Ceroglossus suturalis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"chaetoceros","label":"Chaetoceros","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"chamaecrista fasciculata","label":"Chamaecrista fasciculata","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"chilicola chalcidiformis","label":"Chilicola chalcidiformis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"chitinimonas","label":"Chitinimonas","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"chlamydomonas reinhardtii","label":"Chlamydomonas reinhardtii","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"chromobacterium","label":"Chromobacterium","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"chrysemys picta","label":"Chrysemys picta","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"chrysoperla rufilabris","label":"Chrysoperla rufilabris","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"citrus","label":"Citrus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"clavibacter sp.","label":"Clavibacter sp.","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"colinus virginianus","label":"Colinus virginianus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"crassostrea virginica","label":"Crassostrea virginica","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"crithidia fasciculata","label":"Crithidia fasciculata","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"cutibacterium acnes","label":"Cutibacterium acnes","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"cyanobacteria","label":"Cyanobacteria","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"daphnia","label":"Daphnia","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"daphnia pulex","label":"Daphnia pulex","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"diabrotica virgifera","label":"Diabrotica virgifera","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"diabrotica virgifera virgifera virus 1","label":"Diabrotica virgifera virgifera virus 1","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"d. discoideum","label":"Dictyostelium discoideum","imageSrc":"dicty.png","imageAlt":"D. discoideum","mod":"dictyBase","modLink":"http://dictybase.org","linkVariable":""},{"value":"diptera","label":"Diptera","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"dotocryptus bellicosus","label":"Dotocryptus bellicosus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"drechmeria coniospora","label":"Drechmeria coniospora","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"drosophila","label":"Drosophila","imageSrc":"drosophila.png","imageAlt":"Drosophila graphic by Zoe Zorn CC BY 4.0","mod":"FlyBase","modLink":"https://flybase.org/doi/","linkVariable":"doi"},{"value":"dryopteris campyloptera","label":"Dryopteris campyloptera","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"dryopteris expansa","label":"Dryopteris expansa","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"dryopteris intermedia","label":"Dryopteris intermedia","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"dugesia dorotocephala","label":"Dugesia dorotocephala","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"elasmobranchii","label":"Elasmobranchii","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"embryophyta","label":"Embryophyta","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"enoploteuthis chunii","label":"Enoploteuthis chunii","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"enterobacter aerogenes","label":"Enterobacter aerogenes","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"enterococcus raffinosus","label":"Enterococcus raffinosus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"epichloë coenophiala","label":"Epichloë coenophiala","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"equus caballus","label":"Equus caballus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"erigeron sp","label":"Erigeron sp","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"eristalis","label":"Eristalis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"eruca vesicaria","label":"Eruca vesicaria","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"erwinia carotovora","label":"Erwinia carotovora","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"erythronium americanum","label":"Erythronium americanum","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"escherichia coli","label":"Escherichia coli","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"eukaryota","label":"Eukaryotes","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"felis catus","label":"Felis catus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"francisella novicida","label":"Francisella novicida","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"francisella tularensis","label":"Francisella tularensis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"fraxinus americana","label":"Fraxinus americana","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"fucus distichus","label":"Fucus distichus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"fungi","label":"Fungi","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"gasteropelecus sp.","label":"Gasteropelecus sp.","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"geranium sp","label":"Geranium sp","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"girardia","label":"Girardia","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"glaucomys volans","label":"Glaucomys volans","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"glycine max","label":"Glycine max","imageSrc":"","imageAlt":"","mod":"Soybase","modLink":"https://soybase.org","linkVariable":""},{"value":"glyptemys insculpta","label":"Glyptemys insculpta","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"gossypium hirsutum","label":"Gossypium hirsutum","imageSrc":"","imageAlt":"","mod":"CottonGen","modLink":"https://www.cottongen.org/","linkVariable":""},{"value":"gromphadorhina portentosa","label":"Gromphadorhina portentosa","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"gryllodes sigillatus","label":"Gryllodes sigillatus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"haliotis rufescens","label":"Haliotis rufescens","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"hepacivirus hominis","label":"Hepatitis C Virus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"herpes simplex virus type 1","label":"Herpes simplex virus type 1","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"human","label":"Human","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"human coronavirus oc43","label":"Human coronavirus OC43","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"hydra vulgaris","label":"Hydra vulgaris","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"hydropsyche sp","label":"Hydropsyche sp","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"hymenoptera","label":"Hymenoptera","imageSrc":"","imageAlt":"","mod":"Hymenoptera Genome Database","modLink":"https://hymenoptera.elsiklab.missouri.edu/","linkVariable":""},{"value":"hypochaeris radicata","label":"Hypochaeris radicata","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"hypodynerus vespiformis","label":"Hypodynerus vespiformis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"iflaviridae","label":"Iflaviridae","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"iflavuris","label":"Iflavirus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ipomoea hederacea","label":"Ipomoea hederacea","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ischnomera","label":"Ischnomera","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ischnomera ruficollis","label":"Ischnomera ruficollis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"julidochromis marlieri","label":"Julidochromis marlieri","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"juniperus virginiana","label":"Juniperus virginiana","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"kluyveromyces marxianus","label":"Kluyveromyces marxianus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"l. casei","label":"L. casei","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"lacticaseibacillus casei","label":"Lacticaseibacillus casei","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"larentiinae sp","label":"Larentiinae sp","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"laurus nobilis","label":"Laurus nobilis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"lepidoptera","label":"Lepidoptera","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"leucanthemum vulgare","label":"Leucanthemum vulgare","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"linepithema humile","label":"Linepithema humile","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"liometopum occidentale","label":"Liometopum occidentale","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"lolium arundinaceum","label":"Lolium arundinaceum","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"lumbriculus variegatus","label":"Lumbriculus variegatus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"lumbricus terrestris","label":"Lumbricus terrestris","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"lupinus polyphyllus","label":"Lupinus polyphyllus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"lycorma delicatula","label":"Lycorma delicatula","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"lynx rufus","label":"Lynx rufus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"magnaporthe oryzae","label":"Magnaporthe oryzae","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"mammalia","label":"Mammalia","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"manihot esculenta","label":"Manihot esculenta","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"medicago lupulina","label":"Medicago lupulina","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"meloidogyne","label":"Meloidogyne","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"mimus polyglottos","label":"Mimus polyglottos","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"bryophyta","label":"Mosses","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"mouse","label":"Mouse","imageSrc":"","imageAlt":"","mod":"MGI","modLink":"https://informatics.jax.org","linkVariable":""},{"value":"m. minutoides","label":"Mus minutoides","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"mycobacterium smegmatis","label":"Mycobacterium smegmatis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"nakaseomyces glabratus","label":"Nakaseomyces glabratus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"nauphoeta cinerea","label":"Nauphoeta cinerea","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"neurospora","label":"Neurospora","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"n. benthamiana","label":"Nicotiana benthamiana","imageSrc":"","imageAlt":"","mod":"Solgenomics Network","modLink":"https://solgenomics.net/organism/Nicotiana_benthamiana/genome","linkVariable":""},{"value":"nicotiana tabacum","label":"Nicotiana tabacum","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"noctuidae","label":"Noctuidae","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"noctuidae sp","label":"Noctuidae sp","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"nothobranchius furzeri","label":"Nothobranchius furzeri","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"onchocerca volvulus","label":"Onchocerca volvulus","imageSrc":"","imageAlt":"","mod":"WormBase","modLink":"www.wormbase.org","linkVariable":""},{"value":"orconectes virilis","label":"Orconectes virilis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ormia ochracea","label":"Ormia ochracea","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"o. sativa","label":"Oryza sativa","imageSrc":"","imageAlt":"","mod":"Gramene","modLink":"https://www.gramene.org/","linkVariable":""},{"value":"other","label":"Other","imageSrc":"","imageAlt":"","mod":null,"modLink":null,"linkVariable":null},{"value":"oxalis enneaphylla","label":"Oxalis enneaphylla","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"paenarthrobacter nicotinovorans","label":"Paenarthrobacter nicotinovorans","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"paenarthrobacter nicotinovorans","label":"Paenarthrobacter nicotinovorans","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"pantoea","label":"Pantoea","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"pantoea agglomerans","label":"Pantoea agglomerans","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"papaver sp","label":"Papaver sp","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"paramecium bursaria","label":"Paramecium bursaria","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"partitiviridae","label":"Partitiviridae","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"pelodiscus sinensis","label":"Pelodiscus sinensis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"perezia recurvata","label":"Perezia recurvata","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"petromyzon marinus","label":"Petromyzon marinus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"photinus pyralis","label":"Photinus pyralis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"photinus pyralis associated partiti-like virus","label":"Photinus pyralis associated partiti-like virus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"photinus pyralis iflavirus 1","label":"Photinus pyralis iflavirus 1","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"physcomitrium patens","label":"Physcomitrium patens","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"pinus strobus","label":"Pinus strobus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"pinus taeda","label":"Pinus taeda","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"platycheirus","label":"Platycheirus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"plectus sambesii","label":"Plectus sambesii","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"pogonomyrmex occidentalis","label":"Pogonomyrmex occidentalis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"poncirus trifoliata","label":"Poncirus trifoliata","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"populus deltoides","label":"Populus deltoides","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"potato virus y","label":"Potato virus Y","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"primula magellanica","label":"Primula magellanica","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"pristionchus pacificus","label":"Pristionchus pacificus","imageSrc":"","imageAlt":"","mod":"WormBase","modLink":"www.wormbase.org","linkVariable":""},{"value":"prunus persica","label":"Prunus persica","imageSrc":"","imageAlt":"","mod":"Genome Database for Rosaceae","modLink":"https://www.rosaceae.org/","linkVariable":""},{"value":"psalmopoeus iriminia","label":"Psalmopoeus iriminia","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"pseudanabaena sp.","label":"Pseudanabaena sp.","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"pseudomonas","label":"Pseudomonas","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"pseudomonas aeruginosa","label":"Pseudomonas aeruginosa","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"pseudomonas glycinae","label":"Pseudomonas glycinae","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"pseudomonas putida","label":"Pseudomonas putida","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"pseudomonas syringae","label":"Pseudomonas syringae","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"pterophyllum scalare","label":"Pterophyllum scalare","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"python regius","label":"Python regius","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"quercus macrocarpa","label":"Quercus macrocarpa","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ralstonia solanacearum","label":"Ralstonia solanacearum","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ranitomeya imitator","label":"Ranitomeya imitator","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ranunculus peduncularis","label":"Ranunculus peduncularis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"rat","label":"Rat","imageSrc":"","imageAlt":"","mod":"RGD","modLink":"https://rgd.mcw.edu","linkVariable":""},{"value":"rheinheimera","label":"Rheinheimera","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ribes rubrum","label":"Ribes rubrum","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"sars-cov-2","label":"SARS-CoV-2","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"s. cerevisiae","label":"Saccharomyces cerevisiae","imageSrc":"yeast.png","imageAlt":"Yeast graphic by Zoe Zorn CC BY 4.0","mod":"SGD","modLink":"https://yeastgenome.org","linkVariable":""},{"value":"saccharomyces paradoxus","label":"Saccharomyces paradoxus ","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"s. uvarum","label":"Saccharomyces uvarum","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"schistosoma","label":"Schistosoma","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"schizosaccharomyces japonicus","label":"Schizosaccharomyces japonicus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"s. pombe","label":"Schizosaccharomyces pombe","imageSrc":"pombe.png","imageAlt":"Pombe graphic by Zoe Zorn © Caltech","mod":"PomBase","modLink":"https://www.pombase.org/reference/PMID:","linkVariable":"pmId"},{"value":"schmidtea mediterranea","label":"Schmidtea mediterranea","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"senecio sp","label":"Senecio sp","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"simocephalus","label":"Simocephalus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"siraitia grosvenorii","label":"Siraitia grosvenorii","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"solanum lycopersicum","label":"Solanum lycopersicum","imageSrc":"","imageAlt":"","mod":"Solgenomics Network","modLink":"https://solgenomics.net/organism/1/view/","linkVariable":""},{"value":"sorghum","label":"Sorghum","imageSrc":"","imageAlt":"","mod":"SorghumBase","modLink":"https://www.sorghumbase.org","linkVariable":""},{"value":"spiroplasma eriocheiris","label":"Spiroplasma eriocheiris","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"staphylococcus aureus","label":"Staphylococcus aureus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"staphylococcus epidermidis","label":"Staphylococcus epidermidis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"steinernema carpocapsae","label":"Steinernema carpocapsae","imageSrc":"","imageAlt":"","mod":"WormBase","modLink":"https://wormbase.org","linkVariable":""},{"value":"steinernema hermaphroditum","label":"Steinernema hermaphroditum","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"stenotrophomonas geniculata","label":"Stenotrophomonas geniculata","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"streptococcus gordonii ","label":"Streptococcus gordonii ","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"streptococcus mutans","label":"Streptococcus mutans","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":" streptococcus pneumoniae","label":"Streptococcus pneumoniae","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"s. purpuratus","label":"Strongylocentrotus purpuratus","imageSrc":"","imageAlt":"","mod":"Echinobase","modLink":"https://www.echinobase.org","linkVariable":""},{"value":"strongyloides ratti","label":"Strongyloides ratti","imageSrc":"","imageAlt":"","mod":"WormBase","modLink":"www.wormbase.org","linkVariable":""},{"value":"sulfolobus","label":"Sulfolobus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"symphoricarpos albus","label":"Symphoricarpos albus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"syncirsodes","label":"Syncirsodes","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"synechococcus elongatus","label":"Synechococcus elongatus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"syrphidae","label":"Syrphidae","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"tarantobelus jeffdanielsi","label":"Tarantobelus jeffdanielsi","imageSrc":"","imageAlt":"","mod":"WormBase","modLink":"www.wormbase.org","linkVariable":""},{"value":"taraxacum officinale","label":"Taraxacum officinale","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"tatochila theodice","label":"Tatochila theodice","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"tetrahymena","label":"Tetrahymena","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"tetramorium immigrans","label":"Tetramorium immigrans","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"tomato brown rugose fruit virus","label":"ToBRFV","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"trachemys scripta","label":"Trachemys scripta","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"tribolium castaneum","label":"Tribolium castaneum","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"trichoptera","label":"Trichoptera","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"trichuris muris","label":"Trichuris muris","imageSrc":"","imageAlt":"","mod":"WormBase","modLink":"www.wormbase.org","linkVariable":""},{"value":"trifolium repens","label":"Trifolium repens","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"trypoxylus dichotomus","label":"Trypoxylus dichotomus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"tsuga canadensis","label":"Tsuga canadensis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ulva expansa","label":"Ulva expansa","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"universal","label":"Universal","imageSrc":"","imageAlt":"","mod":null,"modLink":null,"linkVariable":null},{"value":"vargula hilgendorfii","label":"Vargula hilgendorfii","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"vespula vulgaris","label":"Vespula vulgaris","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"virus","label":"Virus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"watasenia scintillans","label":"Watasenia scintillans","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"wolbachia pipientis","label":"Wolbachia pipientis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"xenopus","label":"Xenopus","imageSrc":"xenopus.png","imageAlt":"Xenopus graphic by Zoe Zorn CC BY 4.0","mod":"XenBase","modLink":"https://xenbase.org","linkVariable":""},{"value":"xenorhabdus griffiniae","label":"Xenorhabdus griffiniae","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"yramea cytheris","label":"Yramea cytheris","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"zaprionus indianus","label":"Zaprionus indianus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"zea mays","label":"Zea mays","imageSrc":"","imageAlt":"","mod":"MaizeGDB","modLink":"https://www.maizegdb.org","linkVariable":""},{"value":"zebrafish","label":"Zebrafish","imageSrc":"zebrafish.png","imageAlt":"Zebrafish graphic by Zoe Zorn CC BY 4.0","mod":"ZFIN","modLink":"https://zfin.org","linkVariable":""}]}},"pageContext":{"id":"3f6a9f26-d915-439b-b8c2-c46bc8c517a7","citedBy":[],"parsedCsv":{"csvHeader":[],"csvData":[]}}}, "staticQueryHashes": ["2114697108"]}