Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a key negative regulator of T-cell activation in the vertebrate adaptive immune system. Mutations in Ptpn22 are associated with human autoimmunity and mouse anti-viral immunity. In vertebrates, Ptpn22 expression is predominantly in lymphoid cells. In C. elegans, ptpn-22 encodes a molecule similar to vertebrate PTPN22, but lacks the domain involved in vertebrate autoimmunity and anti-viral activity. ptpn-22 is expressed broadly in C. elegans, including in hypodermis, neurons, and the Q neuroblasts, and regulates the formation of epidermal desmosomal adhesion complexes and cuticular molting. In this work we show that PTPN-22 is required for migration of the AQR and PQR neurons, a novel role for the Ptpn22 family of molecules. ptpn-22 mutants displayed a failure of AQR and PQR neurons to migrate anteriorly and posteriorly respectively, but did not affect direction of migration. Vertebrate PTPN22 is involved in T cell migration and in the formation of the “immune synapse” adhesion complex. Our results along with those reported previously suggest an ancestral role of the PTPN22 family in cell adhesion and migration.
","acknowledgements":"The authors thank D. Fay for sharing the ptpn-22 mutant strains. Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440).
","authors":[{"affiliations":["University of Kansas, Lawrence, KS, United States"],"departments":["Molecular Biosciences"],"credit":["formalAnalysis","investigation","visualization","writing_originalDraft"],"email":"myori01@ku.edu","firstName":"Mark","lastName":"Yorio","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"0009-0000-8084-0082"},{"affiliations":["University of Kansas, Lawrence, Kansas, United States"],"departments":["Molecular Biosciences"],"credit":["conceptualization","dataCuration","fundingAcquisition","investigation","methodology","formalAnalysis","project","writing_reviewEditing"],"email":"erikl@ku.edu","firstName":"Erik","lastName":"Lundquist","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"0000-0001-6819-4815"}],"awards":[{"awardId":"R01-NS115467","funderName":"National Institute of Neurological Disorders and Stroke (United States)","awardRecipient":"Erik Lundquist"}],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"","image":{"url":"https://portal.micropublication.org/uploads/99c182f0932f3a3f5e4b42b3928acea7.png"},"imageCaption":"Figure 1. AQR and PQR migration defects in ptpn-22 mutants. A) A schematic of the QR and QL (QX) neuroblast lineage in the early L1 larva. The X axis is anterior to posterior, and the Y axis is time. A small “a” indicates the anterior daughter of a cell division, and a small “p” indicates the posterior daughter. Small grey circles indicate cells that undergo programmed cell death. B) UMAP coordinates for single-cell RNA-seq of the Q lineage indicating ptpn-22 expression (see Methods). Cells are colored by expression level (purple), with gray indicating undetectable expression. C-D) The lqIs244[Pgcy-32::cfp] transgene was used to visualize the URX, AQR and PQR neurons. For each animal, Anterior (A), posterior (P), dorsal (D), and ventral (V) are indicated by arrows. The scale bar in C represents 10μm for both C and D. C) A wild type larva with lqIs244[gcy-32::cfp] expression. AQR is located in the anterior deirid ganglion near the posterior pharyngeal bulb (arrow). PQR is located posterior to the anus in the phasmid ganglion (arrow). The red box inset is a magnified view of PQR position posterior to the anus (dashed line and arrowhead). D) ptpn-22(fd388) mutant L4 larvae with lqIs244[gcy-32::cfp] expression. In the top animal. PQR has failed to migrate posterior to the anus (arrow). The red box inset is a magnified view of PQR located immediately anterior to the anus (arrowhead and dashed line). The asterisk indicates the normal position of PQR. In the bottom animal, AQR has failed to migrate anteriorly to the anterior deirid and is instead displaced posteriorly behind the posterior pharyngeal bulb. The asterisk indicates the normal position of AQR. E) Quantification of AQR and PQR defects. The table indicates the positions of AQR and PQR in wild-type and ptpn-22 mutants. The figure above the table shows the five positions along the anterior-posterior axis of the animal that were used to score AQR and PQR position. For each genotype, 100 animals were scored. The asterisks indicate that the AQR defects in the mutants were significantly less severe than those in ptpn-22(fd388) and ptpn-22(fd406) (p < 0.03).
","imageTitle":"ptpn-22 mutants displays AQR and PQR migration defects
","methods":"Methods
C. elegans strains were maintained and scored at 20°C. AQR and PQR were visualized using the Pgcy-32::cfp transgene lqIs244 16, 19 (Chapman et al. 2008; Josephson et al. 2016). AQR and PQR positions along the body were noted using a five-position scale as previously described 19, 21, 22 (See Fig 1E). Statistical significance was determined using Fisher's Exact test.
","reagents":"Reagents
The following C. elegans mutants and transgenes were used: LGII, lqIs244[Pgcy-32::cfp]; LGIV, ptpn-22(gk194708), ptpn-22(gk3186), ptpn-22(fd331), ptpn-22(fd388), ptpn-22(fd406). The tmC25 balancer 27 was used to isolate ptpn-22 mutant chromosomes. The presence of ptpn-22 mutations was confirmed by sequencing or PCR genotyping. The following strains were analyzed:
Strain | Genotype | Origin |
LE3885 | lqIs244 II | 19 |
LE8131 | ptpn-22(gk194708) IV; lqIs244 II | 1 and this work |
LE8130 | ptpn-22(gk3186) IV; lqIs244 II | 1 and this work |
LE8128 | ptpn-22(fd331) IV; lqIs244 II | 1 and this work |
LE8127 | ptpn-22(fd388) IV; lqIs244 II | 1 and this work |
LE8129 | ptpn-22(fd406) IV; lqIs244 II | 1 and this work |
","patternDescription":"
C. elegans PTPN-22 is an ortholog of vertebrate the vertebrate protein tyrosine phosphatase non-receptor type 22 PTPN22 1-3. PTPN22 has been investigated in mammalian systems for its roles in lymphoid and immune function 3-5, notably suppression of T cell activation 6 and viral immunity 7, 8. In human populations, Ptpn22 variants are associated with autoimmune disorders 9, 10. In humans, Ptpn22 is expressed strongly in lymphoid tissues, with lower expression in other tissue types 11, 12. In C. elegans, mutations in ptpn-22 have been shown to suppress cuticular molting defects due to mutations in NIMA-like kinases NEKL-2 and NEKL-3, and to be associated with hypodermal adhesion complexes including hemidesmosomes 1.
Single-cell RNA sequencing of the Q neuroblast lineage shows that ptpn-22 is expressed throughout the Q neuroblast lineages as they develop (Figure 1A and B) 13. The bilateral Q neuroblasts, are derived embryonically and migrate in the L1 larva after hatching 14-18. QR on the right migrates anteriorly over the V4 seam cell, and QL on the left migrates posteriorly over the V5 seam cell 16. A similar pattern of cell division, programmed cell death, and neuronal differentiation results in three neurons on each side: AQR, AVM, and SDQR on the right, and PQR, PVM, and SDQL on the left. The QR descendant AQR migrate farthest anteriorly to the deirid ganglion near the pharynx (Figure 1C). The QL descendant PQR migrates the farthest posteriorly to the phasmid ganglion posterior to the anus (Figure 1C). Mutations that disrupt Q lineage migrations result in misplaced AQR and/or PQR neurons. Directional defects in migration (e.g. anterior PQR migration or posterior AQR migration) result from mutations that affect the first Q cell migration and subsequent Wnt-mediated activation of the Hox transcription factor MAB-5/Antennapedia 19. Failure of migration (e.g. AQR and PQR migrate in the correct direction but do not complete migration) can result from disruption of the migration substrate such as epi-1/Laminin-α5 mutation 20, or from mutation of downstream target genes of MAB-5/Antennapedia 21, 22.
We analyzed AQR and PQR migration in five ptpn-22 alleles 1. All five alleles showed failure of complete AQR migration (9-33%) (Figure 1D and E). PQR migration failure was noted in three of the five mutants (0-6%) (Figure 1D and E). No directional migration defects were noted. Rather, AQR and PQR migrated in the correct direction but failed complete migration. Misplaced AQR were displaced posteriorly behind the pharynx, and misplaced PQR were displaced anteriorly, immediately anterior to the anus (Figure 1D). This phenotype is consistent with failure of the third migration of QL.ap/PQR posterior to the anus 21, 22, and might also represent a late-stage failure of QR.ap/AQR migration 14, 17. ptpn-22(fd388) introduces a premature stop codon in the second codon exon, and ptpn-22(fd406) is a cysteine to serine missense mutation in the phosphatase catalytic domain 1. These two mutants displayed significantly stronger AQR migration defects compared to the other three alleles analyzed (fd331, a frameshift; gk3186, a deletion of the first two coding exons; and gk194708, a premature stop codon in the second to last codon exon)1, 23. Each of these is predicted to be a complete loss-of-function, and it is unclear why they have a significantly weaker phenotype than ptpn-22(fd388). This could be due to the genetic background of ptpn-22(fd388), or to retention of some function in fd331, gk3186, and gk194708. The catalytically-dead ptpn-22(fd406) could be significantly stronger because of a potential dominant-negative function (i.e. the molecule might interact with binding partners leading to a non-functional complex). In sum, these results indicate that PTPN-22 is required for migration of the AQR and PQR neurons and defines a new function of the Ptpn22 family. While ptpn-22 expression in the Q lineage is likely not controlled by MAB-5/Antennapedia 24, the evidence here could suggest that PTPN-22 is required for the ability of AQR and PQR to migrate fully.
A balance of tyrosine phosphorylation and dephosphorylation is important in QR lineage migrations 25: the SRC-1/Src tyrosine kinase phosphorylates the guidance receptor MIG-13 to regulate actin polymerization in the direction of migration, and the receptor tyrosine phosphatase PTP-3/LAR is responsible for mitigating this in the rear of the migrating cells. Src kinases are key substrates for PTPN22 activity in the immune system 6, 26. It is possible that PTPN-22 participates in this tyrosine phosphorylation balance underlying AQR and PQR migration via modulating cytoskeletal or cell adhesion functions. In any case, these results are consistent with an ancestral role of PTPN22 family members in regulating cell adhesion and migration.
","references":[{"reference":"Armitage LH, Wallet MA, Mathews CE. 2021. Influence of PTPN22 Allotypes on Innate and Adaptive Immune Function in Health and Disease. Front Immunol. 12: 636618. 4611.","pubmedId":"33717184","doi":"10.3389/fimmu.2021.636618"},{"reference":"Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP, Alexander HC, et al., Gregersen PK. 2004. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet. 75: 330-7. 4604.","pubmedId":"15208781","doi":"10.1086/422827"},{"reference":"Bevis AM, Rosa K, Schwarting N, Cockerham TR, Kerr CM, More S, Fehr AR, Orozco RC. 2026. An autoimmunity-associated allele of PTPN22 enhances innate antiviral immunity to protect against acute coronavirus infection. Proc Natl Acad Sci U S A. 123: e2519903123. 4608.","pubmedId":"41849391","doi":"10.1073/pnas.2519903123"},{"reference":"Binti S, Linder AG, Edeen PT, Fay DS. 2024. A conserved protein tyrosine phosphatase, PTPN-22, functions in diverse developmental processes in C. elegans. PLoS Genet. 20: e1011219. 4603.","pubmedId":"39173071","doi":"10.1371/journal.pgen.1011219"},{"reference":"Bottini N, Peterson EJ. 2014. Tyrosine phosphatase PTPN22: multifunctional regulator of immune signaling, development, and disease. Annu Rev Immunol. 32: 83-119. 4609.","pubmedId":"24364806","doi":"10.1146/annurev-immunol-032713-120249"},{"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: 245-57. 1311.","pubmedId":"18840424","doi":"10.1016/j.ydbio.2008.09.014"},{"reference":"Cloutier JF, Veillette A. 1999. Cooperative inhibition of T-cell antigen receptor signaling by a complex between a kinase and a phosphatase. 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EFN-4/Ephrin converges with SAX-3/Robo, UNC-6/Netrin, and Heparan Sulfate Proteoglycan signaling to control MAB-5/Hox-dependent posterior Q neuroblast migration in Caenorhabditis elegans. bioRxiv 4584.","pubmedId":"41959263","doi":"10.64898/2026.03.27.714887"},{"reference":"Jain VD, Lundquist EA. 2025. VAB-8/KIF26, LIN-17/Frizzled, and EFN-4/Ephrin, control distinct stages of posterior neuroblast migration downstream of the MAB-5/Hox transcription factor in Caenorhabditis elegans. PLoS Genet. 21: e1011906. 4523.","pubmedId":"41071838","doi":"10.1371/journal.pgen.1011906"},{"reference":"Josephson MP, Chai Y, Ou G, Lundquist EA. 2016. EGL-20/Wnt and MAB-5/Hox Act Sequentially to Inhibit Anterior Migration of Neuroblasts in C. elegans. PLoS One. 11: e0148658. 3455.","pubmedId":"26863303","doi":"10.1371/journal.pone.0148658"},{"reference":"Lang AE, Lundquist EA. 2021. The Collagens DPY-17 and SQT-3 Direct Anterior-Posterior Migration of the Q Neuroblasts in C. elegans. 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The Caenorhabditis elegans Q neuroblasts: A powerful system to study cell migration at single-cell resolution in vivo. Genesis. 54: 198-211. 4432.","pubmedId":"26934462","doi":"10.1002/dvg.22931"},{"reference":"Schild ES, Gupta S, Dubois C, Fernandes Povoa EE, Felix MA, Mugler A, Korswagen HC. 2023. Precise temporal control of neuroblast migration through combined regulation and feedback of a Wnt receptor. Elife. 12 4615.","pubmedId":"37184061","doi":"10.7554/eLife.82675"},{"reference":"Sulston JE. 1976. Post-embryonic development in the ventral cord of Caenorhabditis elegans. Philos. Trans. R. Soc. Lond. [Biol]. 275: 287-297. 547.","pubmedId":"","doi":""},{"reference":"Teixeira FL, Sanderson B, Hackett JL, Lundquist EA. 2026. Single-cell transcriptomic profiling of C. elegans Q neuroblast lineage during migration and differentiation. PLoS One. 21: e0343734. 4576.","pubmedId":"41774717","doi":"10.1371/journal.pone.0343734"},{"reference":"Thompson O, Edgley M, Strasbourger P, Flibotte S, Ewing B, Adair R, et al., Waterston RH. 2013. The million mutation project: a new approach to genetics in Caenorhabditis elegans. Genome Res. 23: 1749-62. 2613.","pubmedId":"23800452","doi":"10.1101/gr.157651.113"},{"reference":"Thul PJ, Akesson L, Wiking M, Mahdessian D, Geladaki A, Ait Blal H, et al., Lundberg E. 2017. A subcellular map of the human proteome. Science. 356 4613.","pubmedId":"28495876","doi":"10.1126/science.aal3321"},{"reference":"Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, et al., Ponten F. 2015. Proteomics. Tissue-based map of the human proteome. Science. 347: 1260419. 4614.","pubmedId":"25613900","doi":"10.1126/science.1260419"},{"reference":"Wu J, Katrekar A, Honigberg LA, Smith AM, Conn MT, Tang J, et al., Clark JM. 2006. Identification of substrates of human protein-tyrosine phosphatase PTPN22. J Biol Chem. 281: 11002-10. 4617.","pubmedId":"16461343","doi":"10.1074/jbc.M600498200"},{"reference":"Zhu Z, Chai Y, Hu H, Li W, Li WJ, Dong MQ, et al., Ou G. 2020. Spatial confinement of receptor activity by tyrosine phosphatase during directional cell migration. Proc Natl Acad Sci U S A. 117: 14270-14279. 4616.","pubmedId":"32513699","doi":"10.1073/pnas.2003019117"}],"title":"The Caenorhabditis elegans PTPN-22 protein tyrosine phosphatase non-receptor type 22 is required for neuronal migration.
","reviews":[{"reviewer":{"displayName":"David Samuel Fay"},"openAcknowledgement":false,"status":{"submitted":true}}],"curatorReviews":[{"curator":{"displayName":"Gary Craig Schindelman"},"openAcknowledgement":false,"submitted":null}]},{"id":"8447cc0d-82f1-4371-99bb-9385dfe95f62","decision":"revise","abstract":"Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a key negative regulator of T-cell activation in the vertebrate adaptive immune system. Mutations in Ptpn22 are associated with human autoimmunity and mouse anti-viral immunity. In vertebrates, Ptpn22 expression is predominantly in lymphoid cells. In C. elegans, ptpn-22 encodes a molecule similar to vertebrate PTPN22, but lacks the domain involved in vertebrate autoimmunity and anti-viral activity. ptpn-22 is expressed broadly in C. elegans, including in hypodermis, neurons, and the Q neuroblasts, and regulates the formation of epidermal desmosomal adhesion complexes and cuticular molting. In this work we show that PTPN-22 is required for migration of the AQR and PQR neurons, a novel role for the Ptpn22 family of molecules. ptpn-22 mutants displayed a failure of AQR and PQR neurons to migrate anteriorly and posteriorly respectively, but did not affect direction of migration. Vertebrate PTPN22 is involved in T cell migration and in the formation of the “immune synapse” adhesion complex. Our results along with those reported previously suggest an ancestral role of the PTPN22 family in cell adhesion and migration.
","acknowledgements":"The authors thank D. Fay for sharing the ptpn-22 mutant strains. Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440).
","authors":[{"affiliations":["University of Kansas, Lawrence, KS, United States"],"departments":["Molecular Biosciences"],"credit":["formalAnalysis","investigation","visualization","writing_originalDraft"],"email":"myori01@ku.edu","firstName":"Mark","lastName":"Yorio","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"0009-0000-8084-0082"},{"affiliations":["University of Kansas, Lawrence, Kansas, United States"],"departments":["Molecular Biosciences"],"credit":["conceptualization","dataCuration","fundingAcquisition","investigation","methodology","formalAnalysis","project","writing_reviewEditing"],"email":"erikl@ku.edu","firstName":"Erik","lastName":"Lundquist","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"0000-0001-6819-4815"}],"awards":[{"awardId":"R01-NS115467","funderName":"National Institute of Neurological Disorders and Stroke (United States)","awardRecipient":"Erik Lundquist"}],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"","image":{"url":"https://portal.micropublication.org/uploads/99c182f0932f3a3f5e4b42b3928acea7.png"},"imageCaption":"Figure 1. AQR and PQR migration defects in ptpn-22 mutants. A) A schematic of the QR and QL (QX) neuroblast lineage in the early L1 larva. The X axis is anterior to posterior, and the Y axis is time. A small “a” indicates the anterior daughter of a cell division, and a small “p” indicates the posterior daughter. Small grey circles indicate cells that undergo programmed cell death. B) UMAP coordinates for single-cell RNA-seq of the Q lineage indicating ptpn-22 expression (see Methods). Cells are colored by expression level (purple), with gray indicating undetectable expression. C-D) The lqIs244[Pgcy-32::cfp] transgene was used to visualize the URX, AQR and PQR neurons. For each animal, Anterior (A), posterior (P), dorsal (D), and ventral (V) are indicated by arrows. The scale bar in C represents 10μm for both C and D. C) A wild type larva with lqIs244[gcy-32::cfp] expression. AQR is located in the anterior deirid ganglion near the posterior pharyngeal bulb (arrow). PQR is located posterior to the anus in the phasmid ganglion (arrow). The red box inset is a magnified view of PQR position posterior to the anus (dashed line and arrowhead). D) ptpn-22(fd388) mutant L4 larvae with lqIs244[gcy-32::cfp] expression. In the top animal. PQR has failed to migrate posterior to the anus (arrow). The red box inset is a magnified view of PQR located immediately anterior to the anus (arrowhead and dashed line). The asterisk indicates the normal position of PQR. In the bottom animal, AQR has failed to migrate anteriorly to the anterior deirid and is instead displaced posteriorly behind the posterior pharyngeal bulb. The asterisk indicates the normal position of AQR. E) Quantification of AQR and PQR defects. The table indicates the positions of AQR and PQR in wild-type and ptpn-22 mutants. The figure above the table shows the five positions along the anterior-posterior axis of the animal that were used to score AQR and PQR position. For each genotype, 100 animals were scored. The asterisks indicate that the AQR defects in the mutants were significantly less severe than those in ptpn-22(fd388) and ptpn-22(fd406) (p < 0.03).
","imageTitle":"ptpn-22 mutants displays AQR and PQR migration defects
","methods":"C. elegans strains were maintained and scored at 20°C. AQR and PQR were visualized using the Pgcy-32::cfp transgene lqIs244 16, 19 (Chapman et al. 2008; Josephson et al. 2016). AQR and PQR positions along the body were noted using a five-position scale as previously described 19, 21, 22 (See Fig 1E). Statistical significance was determined using Fisher's Exact test.
","reagents":"The following C. elegans mutants and transgenes were used: LGII, lqIs244[Pgcy-32::cfp]; LGIV, ptpn-22(gk194708), ptpn-22(gk3186), ptpn-22(fd331), ptpn-22(fd388), ptpn-22(fd406). The tmC25 balancer 27 was used to isolate ptpn-22 mutant chromosomes. The presence of ptpn-22 mutations was confirmed by sequencing or PCR genotyping. The following strains were analyzed:
Strain | Genotype | Origin |
LE3885 | lqIs244 II | 19 |
LE8131 | ptpn-22(gk194708) IV; lqIs244 II | 1 and this work |
LE8130 | ptpn-22(gk3186) IV; lqIs244 II | 1 and this work |
LE8128 | ptpn-22(fd331) IV; lqIs244 II | 1 and this work |
LE8127 | ptpn-22(fd388) IV; lqIs244 II | 1 and this work |
LE8129 | ptpn-22(fd406) IV; lqIs244 II | 1 and this work |
","patternDescription":"
C. elegans PTPN-22 is an ortholog of vertebrate the vertebrate protein tyrosine phosphatase non-receptor type 22 PTPN22 1-3. PTPN22 has been investigated in mammalian systems for its roles in lymphoid and immune function 3-5, notably suppression of T cell activation 6 and viral immunity 7, 8. In human populations, Ptpn22 variants are associated with autoimmune disorders 9, 10. In humans, Ptpn22 is expressed strongly in lymphoid tissues, with lower expression in other tissue types 11, 12. In C. elegans, mutations in ptpn-22 have been shown to suppress cuticular molting defects due to mutations in NIMA-like kinases NEKL-2 and NEKL-3, and to be associated with hypodermal adhesion complexes including hemidesmosomes 1.
Single-cell RNA sequencing of the Q neuroblast lineage shows that ptpn-22 is expressed throughout the Q neuroblast lineages as they develop (Figure 1A and B) 13. The bilateral Q neuroblasts, are derived embryonically and migrate in the L1 larva after hatching 14-18. QR on the right migrates anteriorly over the V4 seam cell, and QL on the left migrates posteriorly over the V5 seam cell 16. A similar pattern of cell division, programmed cell death, and neuronal differentiation results in three neurons on each side: AQR, AVM, and SDQR on the right, and PQR, PVM, and SDQL on the left. The QR descendant AQR migrate farthest anteriorly to the deirid ganglion near the pharynx (Figure 1C). The QL descendant PQR migrates the farthest posteriorly to the phasmid ganglion posterior to the anus (Figure 1C). Mutations that disrupt Q lineage migrations result in misplaced AQR and/or PQR neurons. Directional defects in migration (e.g. anterior PQR migration or posterior AQR migration) result from mutations that affect the first Q cell migration and subsequent Wnt-mediated activation of the Hox transcription factor MAB-5/Antennapedia 19. Failure of migration (e.g. AQR and PQR migrate in the correct direction but do not complete migration) can result from disruption of the migration substrate such as epi-1/Laminin-α5 mutation 20, or from mutation of downstream target genes of MAB-5/Antennapedia 21, 22.
We analyzed AQR and PQR migration in five ptpn-22 alleles 1. All five alleles showed failure of complete AQR migration (9-33%) (Figure 1D and E). PQR migration failure was noted in three of the five mutants (0-6%) (Figure 1D and E). No directional migration defects were noted. Rather, AQR and PQR migrated in the correct direction but failed complete migration. Misplaced AQR were displaced posteriorly behind the pharynx, and misplaced PQR were displaced anteriorly, immediately anterior to the anus (Figure 1D). This phenotype is consistent with failure of the third migration of QL.ap/PQR posterior to the anus 21, 22, and might also represent a late-stage failure of QR.ap/AQR migration 14, 17. ptpn-22(fd388) introduces a premature stop codon in the second codon exon, and ptpn-22(fd406) is a cysteine to serine missense mutation in the phosphatase catalytic domain 1. These two mutants displayed significantly stronger AQR migration defects compared to the other three alleles analyzed (fd331, a frameshift; gk3186, a deletion of the first two coding exons; and gk194708, a premature stop codon in the second to last codon exon)1, 23. Each of these is predicted to be a complete loss-of-function, and it is unclear why they have a significantly weaker phenotype than ptpn-22(fd388). This could be due to the genetic background of ptpn-22(fd388), or to retention of some function in fd331, gk3186, and gk194708. The catalytically-dead ptpn-22(fd406) could be significantly stronger because of a potential dominant-negative function (i.e. the molecule might interact with binding partners leading to a non-functional complex). In sum, these results indicate that PTPN-22 is required for migration of the AQR and PQR neurons and defines a new function of the Ptpn22 family. While ptpn-22 expression in the Q lineage is likely not controlled by MAB-5/Antennapedia 24, the evidence here could suggest that PTPN-22 is required for the ability of AQR and PQR to migrate fully.
A balance of tyrosine phosphorylation and dephosphorylation is important in QR lineage migrations 25: the SRC-1/Src tyrosine kinase phosphorylates the guidance receptor MIG-13 to regulate actin polymerization in the direction of migration, and the receptor tyrosine phosphatase PTP-3/LAR is responsible for mitigating this in the rear of the migrating cells. Src kinases are key substrates for PTPN22 activity in the immune system 6, 26. It is possible that PTPN-22 participates in this tyrosine phosphorylation balance underlying AQR and PQR migration via modulating cytoskeletal or cell adhesion functions. In any case, these results are consistent with an ancestral role of PTPN22 family members in regulating cell adhesion and migration.
","references":[{"reference":"Armitage LH, Wallet MA, Mathews CE. 2021. Influence of PTPN22 Allotypes on Innate and Adaptive Immune Function in Health and Disease. Front Immunol. 12: 636618. 4611.","pubmedId":"33717184","doi":"10.3389/fimmu.2021.636618"},{"reference":"Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP, Alexander HC, et al., Gregersen PK. 2004. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet. 75: 330-7. 4604.","pubmedId":"15208781","doi":"10.1086/422827"},{"reference":"Bevis AM, Rosa K, Schwarting N, Cockerham TR, Kerr CM, More S, Fehr AR, Orozco RC. 2026. An autoimmunity-associated allele of PTPN22 enhances innate antiviral immunity to protect against acute coronavirus infection. Proc Natl Acad Sci U S A. 123: e2519903123. 4608.","pubmedId":"41849391","doi":"10.1073/pnas.2519903123"},{"reference":"Binti S, Linder AG, Edeen PT, Fay DS. 2024. A conserved protein tyrosine phosphatase, PTPN-22, functions in diverse developmental processes in C. elegans. PLoS Genet. 20: e1011219. 4603.","pubmedId":"39173071","doi":"10.1371/journal.pgen.1011219"},{"reference":"Bottini N, Peterson EJ. 2014. Tyrosine phosphatase PTPN22: multifunctional regulator of immune signaling, development, and disease. Annu Rev Immunol. 32: 83-119. 4609.","pubmedId":"24364806","doi":"10.1146/annurev-immunol-032713-120249"},{"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: 245-57. 1311.","pubmedId":"18840424","doi":"10.1016/j.ydbio.2008.09.014"},{"reference":"Cloutier JF, Veillette A. 1999. Cooperative inhibition of T-cell antigen receptor signaling by a complex between a kinase and a phosphatase. J Exp Med. 189: 111-21. 4607.","pubmedId":"9874568","doi":"10.1084/jem.189.1.111"},{"reference":"Cohen S, Dadi H, Shaoul E, Sharfe N, Roifman CM. 1999. Cloning and characterization of a lymphoid-specific, inducible human protein tyrosine phosphatase, Lyp. Blood. 93: 2013-24. 4605.","pubmedId":"10068674","doi":""},{"reference":"Gregersen PK, Diamond B, Plenge RM. 2012. GWAS implicates a role for quantitative immune traits and threshold effects in risk for human autoimmune disorders. Curr Opin Immunol. 24: 538-43. 4610.","pubmedId":"23026397","doi":"10.1016/j.coi.2012.09.003"},{"reference":"Hill RJ, Zozulya S, Lu YL, Ward K, Gishizky M, Jallal B. 2002. The lymphoid protein tyrosine phosphatase Lyp interacts with the adaptor molecule Grb2 and functions as a negative regulator of T-cell activation. Exp Hematol. 30: 237-44. 4606.","pubmedId":"11882361","doi":"10.1016/s0301-472x(01)00794-9"},{"reference":"Jain VD, Johannesen AM, Teixeira FL, Lundquist EA. 2026. EFN-4/Ephrin converges with SAX-3/Robo, UNC-6/Netrin, and Heparan Sulfate Proteoglycan signaling to control MAB-5/Hox-dependent posterior Q neuroblast migration in Caenorhabditis elegans. bioRxiv 4584.","pubmedId":"41959263","doi":"10.64898/2026.03.27.714887"},{"reference":"Jain VD, Lundquist EA. 2025. VAB-8/KIF26, LIN-17/Frizzled, and EFN-4/Ephrin, control distinct stages of posterior neuroblast migration downstream of the MAB-5/Hox transcription factor in Caenorhabditis elegans. PLoS Genet. 21: e1011906. 4523.","pubmedId":"41071838","doi":"10.1371/journal.pgen.1011906"},{"reference":"Josephson MP, Chai Y, Ou G, Lundquist EA. 2016. EGL-20/Wnt and MAB-5/Hox Act Sequentially to Inhibit Anterior Migration of Neuroblasts in C. elegans. PLoS One. 11: e0148658. 3455.","pubmedId":"26863303","doi":"10.1371/journal.pone.0148658"},{"reference":"Lang AE, Lundquist EA. 2021. The Collagens DPY-17 and SQT-3 Direct Anterior-Posterior Migration of the Q Neuroblasts in C. elegans. J Dev Biol. 9 4516.","pubmedId":"33669899","doi":"10.3390/jdb9010007"},{"reference":"Middelkoop TC, Korswagen HC. 2014. Development and migration of the C. elegans Q neuroblasts and their descendants. WormBook: 1-23. 2700.","pubmedId":"25317540","doi":"10.1895/wormbook.1.173.1"},{"reference":"Orozco RC, Marquardt K, Pratumchai I, Shaikh AF, Mowen K, Domissy A, Teijaro JR, Sherman LA. 2024. Autoimmunity-associated allele of tyrosine phosphatase gene PTPN22 enhances anti-viral immunity. PLoS Pathog. 20: e1012095. 4612.","pubmedId":"38512979","doi":"10.1371/journal.ppat.1012095"},{"reference":"Paolillo VK, Ochs ME, Lundquist EA. 2024. MAB-5/Hox regulates the Q neuroblast transcriptome, including cwn-1/Wnt, to mediate posterior migration in Caenorhabditis elegans. Genetics. 227 4476.","pubmedId":"38652773","doi":"10.1093/genetics/iyae045"},{"reference":"Rella L, Fernandes Povoa EE, Korswagen HC. 2016. The Caenorhabditis elegans Q neuroblasts: A powerful system to study cell migration at single-cell resolution in vivo. Genesis. 54: 198-211. 4432.","pubmedId":"26934462","doi":"10.1002/dvg.22931"},{"reference":"Schild ES, Gupta S, Dubois C, Fernandes Povoa EE, Felix MA, Mugler A, Korswagen HC. 2023. Precise temporal control of neuroblast migration through combined regulation and feedback of a Wnt receptor. Elife. 12 4615.","pubmedId":"37184061","doi":"10.7554/eLife.82675"},{"reference":"Sulston JE. 1976. Post-embryonic development in the ventral cord of Caenorhabditis elegans. Philos. Trans. R. Soc. Lond. [Biol]. 275: 287-297. 547.","pubmedId":"","doi":""},{"reference":"Teixeira FL, Sanderson B, Hackett JL, Lundquist EA. 2026. Single-cell transcriptomic profiling of C. elegans Q neuroblast lineage during migration and differentiation. PLoS One. 21: e0343734. 4576.","pubmedId":"41774717","doi":"10.1371/journal.pone.0343734"},{"reference":"Thompson O, Edgley M, Strasbourger P, Flibotte S, Ewing B, Adair R, et al., Waterston RH. 2013. The million mutation project: a new approach to genetics in Caenorhabditis elegans. Genome Res. 23: 1749-62. 2613.","pubmedId":"23800452","doi":"10.1101/gr.157651.113"},{"reference":"Thul PJ, Akesson L, Wiking M, Mahdessian D, Geladaki A, Ait Blal H, et al., Lundberg E. 2017. A subcellular map of the human proteome. Science. 356 4613.","pubmedId":"28495876","doi":"10.1126/science.aal3321"},{"reference":"Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, et al., Ponten F. 2015. Proteomics. Tissue-based map of the human proteome. Science. 347: 1260419. 4614.","pubmedId":"25613900","doi":"10.1126/science.1260419"},{"reference":"Wu J, Katrekar A, Honigberg LA, Smith AM, Conn MT, Tang J, et al., Clark JM. 2006. Identification of substrates of human protein-tyrosine phosphatase PTPN22. J Biol Chem. 281: 11002-10. 4617.","pubmedId":"16461343","doi":"10.1074/jbc.M600498200"},{"reference":"Zhu Z, Chai Y, Hu H, Li W, Li WJ, Dong MQ, et al., Ou G. 2020. Spatial confinement of receptor activity by tyrosine phosphatase during directional cell migration. Proc Natl Acad Sci U S A. 117: 14270-14279. 4616.","pubmedId":"32513699","doi":"10.1073/pnas.2003019117"}],"title":"The Caenorhabditis elegans PTPN-22 protein tyrosine phosphatase non-receptor type 22 is required for neuronal migration.
","reviews":[],"curatorReviews":[{"curator":{"displayName":"Gary Craig Schindelman"},"openAcknowledgement":false,"submitted":null}]},{"id":"e951a552-a7f2-48ca-8c1d-c4cde95d5376","decision":"revise","abstract":"PTPN22 is a key negative regulator of T-cell activation in the vertebrate adaptive immune system. Caenorhabditis elegans ptpn-22 encodes a molecule similar to vertebrate PTPN22, is expressed broadly, and regulates the formation of epidermal desmosomal adhesion complexes and cuticular molting. Work here shows that PTPN-22 is required for migration of the AQR and PQR neurons, a novel role for the PTPN22 family of molecules. Our results, along with those reported previously, suggest an ancestral role of the PTPN22 family in cell adhesion and migration, possibly reflected in its role in formation of the immune synapse in vertebrate T cells.
","acknowledgements":"The authors thank D. Fay for sharing the ptpn-22 mutant strains. Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440).
","authors":[{"affiliations":["University of Kansas, Lawrence, KS, United States"],"departments":["Molecular Biosciences"],"credit":["formalAnalysis","investigation","visualization","writing_originalDraft"],"email":"myori01@ku.edu","firstName":"Mark","lastName":"Yorio","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"0009-0000-8084-0082"},{"affiliations":["University of Kansas, Lawrence, Kansas, United States"],"departments":["Molecular Biosciences"],"credit":["conceptualization","dataCuration","fundingAcquisition","investigation","methodology","formalAnalysis","project","writing_reviewEditing"],"email":"erikl@ku.edu","firstName":"Erik","lastName":"Lundquist","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"0000-0001-6819-4815"}],"awards":[{"awardId":"R01-NS115467","funderName":"National Institute of Neurological Disorders and Stroke (United States)","awardRecipient":"Erik Lundquist"}],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"","image":{"url":"https://portal.micropublication.org/uploads/99c182f0932f3a3f5e4b42b3928acea7.png"},"imageCaption":"Figure 1. AQR and PQR migration defects in ptpn-22 mutants. A) A schematic of the QR and QL (QX) neuroblast lineage in the early L1 larva. The X axis is anterior to posterior, and the Y axis is time. A small “a” indicates the anterior daughter of a cell division, and a small “p” indicates the posterior daughter. Small grey circles indicate cells that undergo programmed cell death. B) UMAP coordinates for single-cell RNA-seq of the Q lineage indicating ptpn-22 expression (see Methods). Cells are colored by expression level (purple), with gray indicating undetectable expression. C-D) The lqIs244[Pgcy-32::cfp] transgene was used to visualize the URX, AQR and PQR neurons. For each animal, Anterior (A), posterior (P), dorsal (D), and ventral (V) are indicated by arrows. The scale bar in C represents 10μm for both C and D. C) A wild type larva with lqIs244[gcy-32::cfp] expression. AQR is located in the anterior deirid ganglion near the posterior pharyngeal bulb (arrow). PQR is located posterior to the anus in the phasmid ganglion (arrow). The red box inset is a magnified view of PQR position posterior to the anus (dashed line and arrowhead). D) ptpn-22(fd388) mutant L4 larvae with lqIs244[gcy-32::cfp] expression. In the top animal. PQR has failed to migrate posterior to the anus (arrow). The red box inset is a magnified view of PQR located immediately anterior to the anus (arrowhead and dashed line). The asterisk indicates the normal position of PQR. In the bottom animal, AQR has failed to migrate anteriorly to the anterior deirid and is instead displaced posteriorly behind the posterior pharyngeal bulb. The asterisk indicates the normal position of AQR. E) Quantification of AQR and PQR defects. The table indicates the positions of AQR and PQR in wild-type and ptpn-22 mutants. The figure above the table shows the five positions along the anterior-posterior axis of the animal that were used to score AQR and PQR position. For each genotype, 100 animals were scored. The asterisks indicate that the AQR defects in the mutants were significantly less severe than those in ptpn-22(fd388) and ptpn-22(fd406) (p < 0.03).
","imageTitle":"ptpn-22 mutants displays AQR and PQR migration defects
","methods":"C. elegans strains were maintained and scored at 20°C. AQR and PQR were visualized using the Pgcy-32::cfp transgene lqIs244 16, 19 (Chapman et al. 2008; Josephson et al. 2016). AQR and PQR positions along the body were noted using a five-position scale as previously described 19, 21, 22 (See Fig 1E). Statistical significance was determined using Fisher's Exact test.
","reagents":"The following C. elegans mutants and transgenes were used: LGII, lqIs244[Pgcy-32::cfp]; LGIV, ptpn-22(gk194708), ptpn-22(gk3186), ptpn-22(fd331), ptpn-22(fd388), ptpn-22(fd406). The tmC25 balancer 27 was used to isolate ptpn-22 mutant chromosomes. The presence of ptpn-22 mutations was confirmed by sequencing or PCR genotyping. The following strains were analyzed:
Strain | Genotype | Origin |
lqIs244 II | 19 | |
1 and this work | ||
1 and this work | ||
1 and this work | ||
1 and this work | ||
1 and this work |
","patternDescription":"
C. elegans PTPN-22 is an ortholog of the vertebrate protein tyrosine phosphatase non-receptor type 22 PTPN22 1-3. PTPN22 has been investigated in mammalian systems for its roles in lymphoid and immune function 3-5, notably suppression of T cell activation 6 and viral immunity 7, 8. In human populations, Ptpn22 variants are associated with autoimmune disorders 9, 10. In humans, Ptpn22 is expressed strongly in lymphoid tissues, with lower expression in other tissue types 11, 12. In C. elegans, mutations in ptpn-22 have been shown to suppress cuticular molting defects due to mutations in NIMA-like kinases NEKL-2 and NEKL-3, and to be associated with hypodermal adhesion complexes including hemidesmosomes 1.
Single-cell RNA sequencing of the Q neuroblast lineage shows that ptpn-22 is expressed throughout the Q neuroblast lineages as they develop (Figure 1A and B) 13. The bilateral Q neuroblasts, are derived embryonically and migrate in the L1 larva after hatching 14-18. QR on the right migrates anteriorly over the V4 seam cell, and QL on the left migrates posteriorly over the V5 seam cell 15. A similar pattern of cell division, programmed cell death, and neuronal differentiation results in three neurons on each side: AQR, AVM, and SDQR on the right, and PQR, PVM, and SDQL on the left. The QR descendant AQR migrate farthest anteriorly to the deirid ganglion near the pharynx (Figure 1C). The QL descendant PQR migrates the farthest posteriorly to the phasmid ganglion posterior to the anus (Figure 1C). Mutations that disrupt Q lineage migrations result in misplaced AQR and/or PQR neurons. Directional defects in migration (e.g. anterior PQR migration or posterior AQR migration) result from mutations that affect the first Q cell migration and subsequent Wnt-mediated activation of the Hox transcription factor MAB-5/Antennapedia 19. Failure of migration (e.g. AQR and PQR migrate in the correct direction but do not complete migration) can result from disruption of the migration substrate such as epi-1/Laminin-α5 mutation 20, or from mutation of downstream target genes of MAB-5/Antennapedia 21, 22.
We analyzed AQR and PQR migration in five ptpn-22 alleles 1. All five alleles showed failure of complete AQR migration (9-33%) (Figure 1D and E). PQR migration failure was noted in three of the five mutants (0-6%) (Figure 1D and E). No directional migration defects were noted. Rather, AQR and PQR migrated in the correct direction but failed complete migration. Misplaced AQR were displaced posteriorly behind the pharynx, and misplaced PQR were displaced anteriorly, immediately anterior to the anus (Figure 1D). This phenotype is consistent with failure of the third migration of QL.ap/PQR posterior to the anus 21, 22, and might also represent a late-stage failure of QR.ap/AQR migration 14, 16. ptpn-22(fd388) introduces a premature stop codon in the second codon exon, and ptpn-22(fd406) is a cysteine to serine missense mutation in the phosphatase catalytic domain 1. These two mutants displayed significantly stronger AQR migration defects compared to the other three alleles analyzed (fd331, a frameshift; gk3186, a deletion of the first two coding exons; and gk194708, a premature stop codon in the second to last codon exon)1, 23. Each of these is predicted to be a complete loss-of-function, and it is unclear why they have a significantly weaker phenotype than ptpn-22(fd388). This could be due to the genetic background of ptpn-22(fd388), or to retention of some function in fd331, gk3186, and gk194708. The catalytically-dead ptpn-22(fd406) could be significantly stronger because of a potential dominant-negative function (i.e. the molecule might interact with binding partners leading to a non-functional complex). In sum, these results indicate that PTPN-22 is required for migration of the AQR and PQR neurons and defines a new function of the Ptpn22 family. While ptpn-22 expression in the Q lineage is likely not controlled by MAB-5/Antennapedia 24, the evidence here could suggest that PTPN-22 is required for the ability of AQR and PQR to migrate fully.
A balance of tyrosine phosphorylation and dephosphorylation is important in QR lineage migrations 25: the SRC-1/Src tyrosine kinase phosphorylates the guidance receptor MIG-13 to regulate actin polymerization in the direction of migration, and the receptor tyrosine phosphatase PTP-3/LAR is responsible for mitigating this in the rear of the migrating cells. Src kinases are key substrates for PTPN22 activity in the immune system 6, 26. It is possible that PTPN-22 participates in this tyrosine phosphorylation balance underlying AQR and PQR migration via modulating cytoskeletal or cell adhesion functions. In any case, these results are consistent with an ancestral role of PTPN22 family members in regulating cell adhesion and migration.
","references":[{"reference":"Armitage LH, Wallet MA, Mathews CE. 2021. Influence of PTPN22 Allotypes on Innate and Adaptive Immune Function in Health and Disease. Front Immunol. 12: 636618. 4611.","pubmedId":"33717184","doi":"10.3389/fimmu.2021.636618"},{"reference":"Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP, Alexander HC, et al., Gregersen PK. 2004. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet. 75: 330-7. 4604.","pubmedId":"15208781","doi":"10.1086/422827"},{"reference":"Bevis AM, Rosa K, Schwarting N, Cockerham TR, Kerr CM, More S, Fehr AR, Orozco RC. 2026. An autoimmunity-associated allele of PTPN22 enhances innate antiviral immunity to protect against acute coronavirus infection. Proc Natl Acad Sci U S A. 123: e2519903123. 4608.","pubmedId":"41849391","doi":"10.1073/pnas.2519903123"},{"reference":"Binti S, Linder AG, Edeen PT, Fay DS. 2024. A conserved protein tyrosine phosphatase, PTPN-22, functions in diverse developmental processes in C. elegans. PLoS Genet. 20: e1011219. 4603.","pubmedId":"39173071","doi":"10.1371/journal.pgen.1011219"},{"reference":"Bottini N, Peterson EJ. 2014. Tyrosine phosphatase PTPN22: multifunctional regulator of immune signaling, development, and disease. Annu Rev Immunol. 32: 83-119. 4609.","pubmedId":"24364806","doi":"10.1146/annurev-immunol-032713-120249"},{"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: 245-57. 1311.","pubmedId":"18840424","doi":"10.1016/j.ydbio.2008.09.014"},{"reference":"Cloutier JF, Veillette A. 1999. Cooperative inhibition of T-cell antigen receptor signaling by a complex between a kinase and a phosphatase. J Exp Med. 189: 111-21. 4607.","pubmedId":"9874568","doi":"10.1084/jem.189.1.111"},{"reference":"Cohen S, Dadi H, Shaoul E, Sharfe N, Roifman CM. 1999. Cloning and characterization of a lymphoid-specific, inducible human protein tyrosine phosphatase, Lyp. Blood. 93: 2013-24. 4605.","pubmedId":"10068674","doi":""},{"reference":"Gregersen PK, Diamond B, Plenge RM. 2012. GWAS implicates a role for quantitative immune traits and threshold effects in risk for human autoimmune disorders. Curr Opin Immunol. 24: 538-43. 4610.","pubmedId":"23026397","doi":"10.1016/j.coi.2012.09.003"},{"reference":"Hill RJ, Zozulya S, Lu YL, Ward K, Gishizky M, Jallal B. 2002. The lymphoid protein tyrosine phosphatase Lyp interacts with the adaptor molecule Grb2 and functions as a negative regulator of T-cell activation. Exp Hematol. 30: 237-44. 4606.","pubmedId":"11882361","doi":"10.1016/s0301-472x(01)00794-9"},{"reference":"Jain VD, Johannesen AM, Teixeira FL, Lundquist EA. 2026. EFN-4/Ephrin converges with SAX-3/Robo, UNC-6/Netrin, and Heparan Sulfate Proteoglycan signaling to control MAB-5/Hox-dependent posterior Q neuroblast migration in Caenorhabditis elegans. bioRxiv 4584.","pubmedId":"41959263","doi":"10.64898/2026.03.27.714887"},{"reference":"Jain VD, Lundquist EA. 2025. VAB-8/KIF26, LIN-17/Frizzled, and EFN-4/Ephrin, control distinct stages of posterior neuroblast migration downstream of the MAB-5/Hox transcription factor in Caenorhabditis elegans. PLoS Genet. 21: e1011906. 4523.","pubmedId":"41071838","doi":"10.1371/journal.pgen.1011906"},{"reference":"Josephson MP, Chai Y, Ou G, Lundquist EA. 2016. EGL-20/Wnt and MAB-5/Hox Act Sequentially to Inhibit Anterior Migration of Neuroblasts in C. elegans. PLoS One. 11: e0148658. 3455.","pubmedId":"26863303","doi":"10.1371/journal.pone.0148658"},{"reference":"Lang AE, Lundquist EA. 2021. The Collagens DPY-17 and SQT-3 Direct Anterior-Posterior Migration of the Q Neuroblasts in C. elegans. J Dev Biol. 9 4516.","pubmedId":"33669899","doi":"10.3390/jdb9010007"},{"reference":"Middelkoop TC, Korswagen HC. 2014. Development and migration of the C. elegans Q neuroblasts and their descendants. WormBook: 1-23. 2700.","pubmedId":"25317540","doi":"10.1895/wormbook.1.173.1"},{"reference":"Orozco RC, Marquardt K, Pratumchai I, Shaikh AF, Mowen K, Domissy A, Teijaro JR, Sherman LA. 2024. Autoimmunity-associated allele of tyrosine phosphatase gene PTPN22 enhances anti-viral immunity. PLoS Pathog. 20: e1012095. 4612.","pubmedId":"38512979","doi":"10.1371/journal.ppat.1012095"},{"reference":"Paolillo VK, Ochs ME, Lundquist EA. 2024. MAB-5/Hox regulates the Q neuroblast transcriptome, including cwn-1/Wnt, to mediate posterior migration in Caenorhabditis elegans. Genetics. 227 4476.","pubmedId":"38652773","doi":"10.1093/genetics/iyae045"},{"reference":"Rella L, Fernandes Povoa EE, Korswagen HC. 2016. The Caenorhabditis elegans Q neuroblasts: A powerful system to study cell migration at single-cell resolution in vivo. Genesis. 54: 198-211. 4432.","pubmedId":"26934462","doi":"10.1002/dvg.22931"},{"reference":"Schild ES, Gupta S, Dubois C, Fernandes Povoa EE, Felix MA, Mugler A, Korswagen HC. 2023. Precise temporal control of neuroblast migration through combined regulation and feedback of a Wnt receptor. Elife. 12 4615.","pubmedId":"37184061","doi":"10.7554/eLife.82675"},{"reference":"Sulston JE, Horvitz HR. 1977. Post-embryonic cell lineages of the nematode, Caenorhabditis elegans. Developmental Biology 56: 110-156.
","pubmedId":"838129","doi":" 10.1016/0012-1606(77)90158-0 "},{"reference":"Teixeira FL, Sanderson B, Hackett JL, Lundquist EA. 2026. Single-cell transcriptomic profiling of C. elegans Q neuroblast lineage during migration and differentiation. PLoS One. 21: e0343734. 4576.","pubmedId":"41774717","doi":"10.1371/journal.pone.0343734"},{"reference":"Thompson O, Edgley M, Strasbourger P, Flibotte S, Ewing B, Adair R, et al., Waterston RH. 2013. The million mutation project: a new approach to genetics in Caenorhabditis elegans. Genome Res. 23: 1749-62. 2613.","pubmedId":"23800452","doi":"10.1101/gr.157651.113"},{"reference":"Thul PJ, Akesson L, Wiking M, Mahdessian D, Geladaki A, Ait Blal H, et al., Lundberg E. 2017. A subcellular map of the human proteome. Science. 356 4613.","pubmedId":"28495876","doi":"10.1126/science.aal3321"},{"reference":"Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, et al., Ponten F. 2015. Proteomics. Tissue-based map of the human proteome. Science. 347: 1260419. 4614.","pubmedId":"25613900","doi":"10.1126/science.1260419"},{"reference":"Wu J, Katrekar A, Honigberg LA, Smith AM, Conn MT, Tang J, et al., Clark JM. 2006. Identification of substrates of human protein-tyrosine phosphatase PTPN22. J Biol Chem. 281: 11002-10. 4617.","pubmedId":"16461343","doi":"10.1074/jbc.M600498200"},{"reference":"Zhu Z, Chai Y, Hu H, Li W, Li WJ, Dong MQ, et al., Ou G. 2020. Spatial confinement of receptor activity by tyrosine phosphatase during directional cell migration. Proc Natl Acad Sci U S A. 117: 14270-14279. 4616.","pubmedId":"32513699","doi":"10.1073/pnas.2003019117"}],"title":"The Caenorhabditis elegans PTPN-22 protein tyrosine phosphatase non-receptor type 22 is required for neuronal migration
","reviews":[],"curatorReviews":[{"curator":{"displayName":"Gary Craig Schindelman"},"openAcknowledgement":false,"submitted":"1792704244294"}]},{"id":"4e0dddd4-f62f-438c-bd94-10e2c77866f5","decision":"accept","abstract":"PTPN22 is a key negative regulator of T-cell activation in the vertebrate adaptive immune system. Caenorhabditis elegans ptpn-22 encodes a molecule similar to vertebrate PTPN22, is expressed broadly, and regulates the formation of epidermal desmosomal adhesion complexes and cuticular molting. Work here shows that PTPN-22 is required for migration of the AQR and PQR neurons, a novel role for the PTPN22 family of molecules. Our results, along with those reported previously, suggest an ancestral role of the PTPN22 family in cell adhesion and migration, possibly reflected in its role in formation of the immune synapse in vertebrate T cells.
","acknowledgements":"The authors thank D. Fay for sharing the ptpn-22 mutant strains. Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440).
","authors":[{"affiliations":["University of Kansas, Lawrence, KS, United States"],"departments":["Molecular Biosciences"],"credit":["formalAnalysis","investigation","visualization","writing_originalDraft"],"email":"myori01@ku.edu","firstName":"Mark","lastName":"Yorio","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"0009-0000-8084-0082"},{"affiliations":["University of Kansas, Lawrence, Kansas, United States"],"departments":["Molecular Biosciences"],"credit":["conceptualization","dataCuration","fundingAcquisition","investigation","methodology","formalAnalysis","project","writing_reviewEditing"],"email":"erikl@ku.edu","firstName":"Erik","lastName":"Lundquist","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"0000-0001-6819-4815"}],"awards":[{"awardId":"R01-NS115467","funderName":"National Institute of Neurological Disorders and Stroke (United States)","awardRecipient":"Erik Lundquist"}],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"","image":{"url":"https://portal.micropublication.org/uploads/99c182f0932f3a3f5e4b42b3928acea7.png"},"imageCaption":"Figure 1. AQR and PQR migration defects in ptpn-22 mutants. A) A schematic of the QR and QL (QX) neuroblast lineage in the early L1 larva. The X axis is anterior to posterior, and the Y axis is time. A small “a” indicates the anterior daughter of a cell division, and a small “p” indicates the posterior daughter. Small grey circles indicate cells that undergo programmed cell death. B) UMAP coordinates for single-cell RNA-seq of the Q lineage indicating ptpn-22 expression (see Methods). Cells are colored by expression level (purple), with gray indicating undetectable expression. C-D) The lqIs244[Pgcy-32::cfp] transgene was used to visualize the URX, AQR and PQR neurons. For each animal, Anterior (A), posterior (P), dorsal (D), and ventral (V) are indicated by arrows. The scale bar in C represents 10μm for both C and D. C) A wild type larva with lqIs244[gcy-32::cfp] expression. AQR is located in the anterior deirid ganglion near the posterior pharyngeal bulb (arrow). PQR is located posterior to the anus in the phasmid ganglion (arrow). The red box inset is a magnified view of PQR position posterior to the anus (dashed line and arrowhead). D) ptpn-22(fd388) mutant L4 larvae with lqIs244[gcy-32::cfp] expression. In the top animal. PQR has failed to migrate posterior to the anus (arrow). The red box inset is a magnified view of PQR located immediately anterior to the anus (arrowhead and dashed line). The asterisk indicates the normal position of PQR. In the bottom animal, AQR has failed to migrate anteriorly to the anterior deirid and is instead displaced posteriorly behind the posterior pharyngeal bulb. The asterisk indicates the normal position of AQR. E) Quantification of AQR and PQR defects. The table indicates the positions of AQR and PQR in wild-type and ptpn-22 mutants. The figure above the table shows the five positions along the anterior-posterior axis of the animal that were used to score AQR and PQR position. For each genotype, 100 animals were scored. The asterisks indicate that the AQR defects in the mutants were significantly less severe than those in ptpn-22(fd388) and ptpn-22(fd406) (p < 0.03).
","imageTitle":"ptpn-22 mutants displays AQR and PQR migration defects
","methods":"C. elegans strains were maintained and scored at 20°C. AQR and PQR were visualized using the Pgcy-32::cfp transgene lqIs244 (Chapman et al., 2008; Josephson et al., 2016) (Chapman et al. 2008; Josephson et al. 2016). AQR and PQR positions along the body were noted using a five-position scale as previously described (Jain et al., 2026; Jain & Lundquist, 2025; Josephson et al., 2016) (See Fig 1E). Statistical significance was determined using Fisher's Exact test.
","reagents":"The following C. elegans mutants and transgenes were used: LGII, lqIs244[Pgcy-32::cfp]; LGIV, ptpn-22(gk194708), ptpn-22(gk3186), ptpn-22(fd331), ptpn-22(fd388), ptpn-22(fd406). The tmC25 balancer 27 was used to isolate ptpn-22 mutant chromosomes. The presence of ptpn-22 mutations was confirmed by sequencing or PCR genotyping. The following strains were analyzed:
Strain | Genotype | Origin |
lqIs244 II | (Josephson et al., 2016) | |
(Binti et al., 2024) and this work | ||
(Binti et al., 2024) and this work | ||
(Binti et al., 2024) and this work | ||
(Binti et al., 2024) and this work | ||
(Binti et al., 2024) and this work |
C. elegans PTPN-22 is an ortholog of the vertebrate protein tyrosine phosphatase non-receptor type 22 PTPN22 (Begovich et al., 2004; Binti et al., 2024; Cohen et al., 1999). PTPN22 has been investigated in mammalian systems for its roles in lymphoid and immune function (Bottini & Peterson, 2014; Cohen et al., 1999; Hill et al., 2002), notably suppression of T cell activation (Cloutier & Veillette, 1999) and viral immunity (Bevis et al., 2026; Orozco et al., 2024). In human populations, Ptpn22 variants are associated with autoimmune disorders (Armitage et al., 2021; Gregersen et al., 2012). In humans, Ptpn22 is expressed strongly in lymphoid tissues, with lower expression in other tissue types (Thul et al., 2017; Uhlen et al., 2015). In C. elegans, mutations in ptpn-22 have been shown to suppress cuticular molting defects due to mutations in NIMA-like kinases NEKL-2 and NEKL-3, and to be associated with hypodermal adhesion complexes including hemidesmosomes (Binti et al., 2024).
Single-cell RNA sequencing of the Q neuroblast lineage shows that ptpn-22 is expressed throughout the Q neuroblast lineages as they develop (Figure 1A and B) (Teixeira et al., 2026). The bilateral Q neuroblasts, are derived embryonically and migrate in the L1 larva after hatching (Chapman et al., 2008; Middelkoop & Korswagen, 2014; Rella et al., 2016; Schild et al., 2023; Sulston & Horvitz, 1977). QR on the right migrates anteriorly over the V4 seam cell, and QL on the left migrates posteriorly over the V5 seam cell (Chapman et al., 2008). A similar pattern of cell division, programmed cell death, and neuronal differentiation results in three neurons on each side: AQR, AVM, and SDQR on the right, and PQR, PVM, and SDQL on the left. The QR descendant AQR migrate farthest anteriorly to the deirid ganglion near the pharynx (Figure 1C). The QL descendant PQR migrates the farthest posteriorly to the phasmid ganglion posterior to the anus (Figure 1C). Mutations that disrupt Q lineage migrations result in misplaced AQR and/or PQR neurons. Directional defects in migration (e.g. anterior PQR migration or posterior AQR migration) result from mutations that affect the first Q cell migration and subsequent Wnt-mediated activation of the Hox transcription factor MAB-5/Antennapedia (Josephson et al., 2016). Failure of migration (e.g. AQR and PQR migrate in the correct direction but do not complete migration) can result from disruption of the migration substrate such as epi-1/Laminin-α5 mutation (Lang & Lundquist, 2021), or from mutation of downstream target genes of MAB-5/Antennapedia (Jain et al., 2026; Jain & Lundquist, 2025).
We analyzed AQR and PQR migration in five ptpn-22 alleles (Binti et al., 2024). All five alleles showed failure of complete AQR migration (9-33%) (Figure 1D and E). PQR migration failure was noted in three of the five mutants (0-6%) (Figure 1D and E). No directional migration defects were noted. Rather, AQR and PQR migrated in the correct direction but failed complete migration. Misplaced AQR were displaced posteriorly behind the pharynx, and misplaced PQR were displaced anteriorly, immediately anterior to the anus (Figure 1D). This phenotype is consistent with failure of the third migration of QL.ap/PQR posterior to the anus (Jain et al., 2026; Jain & Lundquist, 2025), and might also represent a late-stage failure of QR.ap/AQR migration (Middelkoop & Korswagen, 2014; Rella et al., 2016). ptpn-22(fd388) introduces a premature stop codon in the second codon exon, and ptpn-22(fd406) is a cysteine to serine missense mutation in the phosphatase catalytic domain (Binti et al., 2024). These two mutants displayed significantly stronger AQR migration defects compared to the other three alleles analyzed (fd331, a frameshift; gk3186, a deletion of the first two coding exons; and gk194708, a premature stop codon in the second to last codon exon) (Binti et al., 2024; Thompson et al., 2013). Each of these is predicted to be a complete loss-of-function, and it is unclear why they have a significantly weaker phenotype than ptpn-22(fd388). This could be due to the genetic background of ptpn-22(fd388), or to retention of some function in fd331, gk3186, and gk194708. The catalytically-dead ptpn-22(fd406) could be significantly stronger because of a potential dominant-negative function (i.e. the molecule might interact with binding partners leading to a non-functional complex). In sum, these results indicate that PTPN-22 is required for migration of the AQR and PQR neurons and defines a new function of the Ptpn22 family. While ptpn-22 expression in the Q lineage is likely not controlled by MAB-5/Antennapedia (Paolillo et al., 2024), the evidence here could suggest that PTPN-22 is required for the ability of AQR and PQR to migrate fully.
A balance of tyrosine phosphorylation and dephosphorylation is important in QR lineage migrations (Zhu et al., 2020): the SRC-1/Src tyrosine kinase phosphorylates the guidance receptor MIG-13 to regulate actin polymerization in the direction of migration, and the receptor tyrosine phosphatase PTP-3/LAR is responsible for mitigating this in the rear of the migrating cells. Src kinases are key substrates for PTPN22 activity in the immune system (Cloutier & Veillette, 1999; Wu et al., 2006). It is possible that PTPN-22 participates in this tyrosine phosphorylation balance underlying AQR and PQR migration via modulating cytoskeletal or cell adhesion functions. In any case, these results are consistent with an ancestral role of PTPN22 family members in regulating cell adhesion and migration.
","references":[{"reference":"Armitage LH, Wallet MA, Mathews CE. 2021. Influence of PTPN22 Allotypes on Innate and Adaptive Immune Function in Health and Disease. Front Immunol. 12: 636618. 4611.","pubmedId":"33717184","doi":"10.3389/fimmu.2021.636618"},{"reference":"Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP, Alexander HC, et al., Gregersen PK. 2004. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet. 75: 330-7. 4604.","pubmedId":"15208781","doi":"10.1086/422827"},{"reference":"Bevis AM, Rosa K, Schwarting N, Cockerham TR, Kerr CM, More S, Fehr AR, Orozco RC. 2026. An autoimmunity-associated allele of PTPN22 enhances innate antiviral immunity to protect against acute coronavirus infection. Proc Natl Acad Sci U S A. 123: e2519903123. 4608.","pubmedId":"41849391","doi":"10.1073/pnas.2519903123"},{"reference":"Binti S, Linder AG, Edeen PT, Fay DS. 2024. A conserved protein tyrosine phosphatase, PTPN-22, functions in diverse developmental processes in C. elegans. PLoS Genet. 20: e1011219. 4603.","pubmedId":"39173071","doi":"10.1371/journal.pgen.1011219"},{"reference":"Bottini N, Peterson EJ. 2014. Tyrosine phosphatase PTPN22: multifunctional regulator of immune signaling, development, and disease. Annu Rev Immunol. 32: 83-119. 4609.","pubmedId":"24364806","doi":"10.1146/annurev-immunol-032713-120249"},{"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: 245-57. 1311.","pubmedId":"18840424","doi":"10.1016/j.ydbio.2008.09.014"},{"reference":"Cloutier JF, Veillette A. 1999. Cooperative inhibition of T-cell antigen receptor signaling by a complex between a kinase and a phosphatase. J Exp Med. 189: 111-21. 4607.","pubmedId":"9874568","doi":"10.1084/jem.189.1.111"},{"reference":"Cohen S, Dadi H, Shaoul E, Sharfe N, Roifman CM. 1999. Cloning and characterization of a lymphoid-specific, inducible human protein tyrosine phosphatase, Lyp. Blood. 93: 2013-24. 4605.","pubmedId":"10068674","doi":""},{"reference":"Gregersen PK, Diamond B, Plenge RM. 2012. GWAS implicates a role for quantitative immune traits and threshold effects in risk for human autoimmune disorders. Curr Opin Immunol. 24: 538-43. 4610.","pubmedId":"23026397","doi":"10.1016/j.coi.2012.09.003"},{"reference":"Hill RJ, Zozulya S, Lu YL, Ward K, Gishizky M, Jallal B. 2002. The lymphoid protein tyrosine phosphatase Lyp interacts with the adaptor molecule Grb2 and functions as a negative regulator of T-cell activation. Exp Hematol. 30: 237-44. 4606.","pubmedId":"11882361","doi":"10.1016/s0301-472x(01)00794-9"},{"reference":"Jain VD, Johannesen AM, Teixeira FL, Lundquist EA. 2026. EFN-4/Ephrin converges with SAX-3/Robo, UNC-6/Netrin, and Heparan Sulfate Proteoglycan signaling to control MAB-5/Hox-dependent posterior Q neuroblast migration in Caenorhabditis elegans. bioRxiv 4584.","pubmedId":"41959263","doi":"10.64898/2026.03.27.714887"},{"reference":"Jain VD, Lundquist EA. 2025. VAB-8/KIF26, LIN-17/Frizzled, and EFN-4/Ephrin, control distinct stages of posterior neuroblast migration downstream of the MAB-5/Hox transcription factor in Caenorhabditis elegans. PLoS Genet. 21: e1011906. 4523.","pubmedId":"41071838","doi":"10.1371/journal.pgen.1011906"},{"reference":"Josephson MP, Chai Y, Ou G, Lundquist EA. 2016. EGL-20/Wnt and MAB-5/Hox Act Sequentially to Inhibit Anterior Migration of Neuroblasts in C. elegans. PLoS One. 11: e0148658. 3455.","pubmedId":"26863303","doi":"10.1371/journal.pone.0148658"},{"reference":"Lang AE, Lundquist EA. 2021. The Collagens DPY-17 and SQT-3 Direct Anterior-Posterior Migration of the Q Neuroblasts in C. elegans. J Dev Biol. 9 4516.","pubmedId":"33669899","doi":"10.3390/jdb9010007"},{"reference":"Middelkoop TC, Korswagen HC. 2014. Development and migration of the C. elegans Q neuroblasts and their descendants. WormBook: 1-23. 2700.","pubmedId":"25317540","doi":"10.1895/wormbook.1.173.1"},{"reference":"Orozco RC, Marquardt K, Pratumchai I, Shaikh AF, Mowen K, Domissy A, Teijaro JR, Sherman LA. 2024. Autoimmunity-associated allele of tyrosine phosphatase gene PTPN22 enhances anti-viral immunity. PLoS Pathog. 20: e1012095. 4612.","pubmedId":"38512979","doi":"10.1371/journal.ppat.1012095"},{"reference":"Paolillo VK, Ochs ME, Lundquist EA. 2024. MAB-5/Hox regulates the Q neuroblast transcriptome, including cwn-1/Wnt, to mediate posterior migration in Caenorhabditis elegans. Genetics. 227 4476.","pubmedId":"38652773","doi":"10.1093/genetics/iyae045"},{"reference":"Rella L, Fernandes Povoa EE, Korswagen HC. 2016. The Caenorhabditis elegans Q neuroblasts: A powerful system to study cell migration at single-cell resolution in vivo. Genesis. 54: 198-211. 4432.","pubmedId":"26934462","doi":"10.1002/dvg.22931"},{"reference":"Schild ES, Gupta S, Dubois C, Fernandes Povoa EE, Felix MA, Mugler A, Korswagen HC. 2023. Precise temporal control of neuroblast migration through combined regulation and feedback of a Wnt receptor. Elife. 12 4615.","pubmedId":"37184061","doi":"10.7554/eLife.82675"},{"reference":"Sulston JE, Horvitz HR. 1977. Post-embryonic cell lineages of the nematode, Caenorhabditis elegans. Developmental Biology 56: 110-156.
","pubmedId":"838129","doi":" 10.1016/0012-1606(77)90158-0 "},{"reference":"Teixeira FL, Sanderson B, Hackett JL, Lundquist EA. 2026. Single-cell transcriptomic profiling of C. elegans Q neuroblast lineage during migration and differentiation. PLoS One. 21: e0343734. 4576.","pubmedId":"41774717","doi":"10.1371/journal.pone.0343734"},{"reference":"Thompson O, Edgley M, Strasbourger P, Flibotte S, Ewing B, Adair R, et al., Waterston RH. 2013. The million mutation project: a new approach to genetics in Caenorhabditis elegans. Genome Res. 23: 1749-62. 2613.","pubmedId":"23800452","doi":"10.1101/gr.157651.113"},{"reference":"Thul PJ, Akesson L, Wiking M, Mahdessian D, Geladaki A, Ait Blal H, et al., Lundberg E. 2017. A subcellular map of the human proteome. Science. 356 4613.","pubmedId":"28495876","doi":"10.1126/science.aal3321"},{"reference":"Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, et al., Ponten F. 2015. Proteomics. Tissue-based map of the human proteome. Science. 347: 1260419. 4614.","pubmedId":"25613900","doi":"10.1126/science.1260419"},{"reference":"Wu J, Katrekar A, Honigberg LA, Smith AM, Conn MT, Tang J, et al., Clark JM. 2006. Identification of substrates of human protein-tyrosine phosphatase PTPN22. J Biol Chem. 281: 11002-10. 4617.","pubmedId":"16461343","doi":"10.1074/jbc.M600498200"},{"reference":"Zhu Z, Chai Y, Hu H, Li W, Li WJ, Dong MQ, et al., Ou G. 2020. Spatial confinement of receptor activity by tyrosine phosphatase during directional cell migration. Proc Natl Acad Sci U S A. 117: 14270-14279. 4616.","pubmedId":"32513699","doi":"10.1073/pnas.2003019117"}],"title":"The Caenorhabditis elegans PTPN-22 protein tyrosine phosphatase non-receptor type 22 is required for neuronal migration
","reviews":[],"curatorReviews":[{"curator":{"displayName":"Gary Craig Schindelman"},"openAcknowledgement":false,"submitted":null}]},{"id":"eedc9537-fd0f-450e-b95d-1f70f3969f38","decision":"publish","abstract":"PTPN22 is a key negative regulator of T-cell activation in the vertebrate adaptive immune system. Caenorhabditis elegans ptpn-22 encodes a molecule similar to vertebrate PTPN22, is expressed broadly, and regulates the formation of epidermal desmosomal adhesion complexes and cuticular molting. Work here shows that PTPN-22 is required for migration of the AQR and PQR neurons, a novel role for the PTPN22 family of molecules. Our results, along with those reported previously, suggest an ancestral role of the PTPN22 family in cell adhesion and migration, possibly reflected in its role in formation of the immune synapse in vertebrate T cells.
","acknowledgements":"The authors thank D. Fay for sharing the ptpn-22 mutant strains. Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440).
","authors":[{"affiliations":["University of Kansas, Lawrence, KS, United States"],"departments":["Molecular Biosciences"],"credit":["formalAnalysis","investigation","visualization","writing_originalDraft"],"email":"myori01@ku.edu","firstName":"Mark","lastName":"Yorio","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"0009-0000-8084-0082"},{"affiliations":["University of Kansas, Lawrence, Kansas, United States"],"departments":["Molecular Biosciences"],"credit":["conceptualization","dataCuration","fundingAcquisition","investigation","methodology","formalAnalysis","project","writing_reviewEditing"],"email":"erikl@ku.edu","firstName":"Erik","lastName":"Lundquist","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"0000-0001-6819-4815"}],"awards":[{"awardId":"R01-NS115467","funderName":"National Institute of Neurological Disorders and Stroke (United States)","awardRecipient":"Erik Lundquist"}],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"","image":{"url":"https://portal.micropublication.org/uploads/99c182f0932f3a3f5e4b42b3928acea7.png"},"imageCaption":"Figure 1. AQR and PQR migration defects in ptpn-22 mutants. A) A schematic of the QR and QL (QX) neuroblast lineage in the early L1 larva. The X axis is anterior to posterior, and the Y axis is time. A small “a” indicates the anterior daughter of a cell division, and a small “p” indicates the posterior daughter. Small grey circles indicate cells that undergo programmed cell death. B) UMAP coordinates for single-cell RNA-seq of the Q lineage indicating ptpn-22 expression (see Methods). Cells are colored by expression level (purple), with gray indicating undetectable expression. C-D) The lqIs244[Pgcy-32::cfp] transgene was used to visualize the URX, AQR and PQR neurons. For each animal, Anterior (A), posterior (P), dorsal (D), and ventral (V) are indicated by arrows. The scale bar in C represents 10μm for both C and D. C) A wild type larva with lqIs244[gcy-32::cfp] expression. AQR is located in the anterior deirid ganglion near the posterior pharyngeal bulb (arrow). PQR is located posterior to the anus in the phasmid ganglion (arrow). The red box inset is a magnified view of PQR position posterior to the anus (dashed line and arrowhead). D) ptpn-22(fd388) mutant L4 larvae with lqIs244[gcy-32::cfp] expression. In the top animal. PQR has failed to migrate posterior to the anus (arrow). The red box inset is a magnified view of PQR located immediately anterior to the anus (arrowhead and dashed line). The asterisk indicates the normal position of PQR. In the bottom animal, AQR has failed to migrate anteriorly to the anterior deirid and is instead displaced posteriorly behind the posterior pharyngeal bulb. The asterisk indicates the normal position of AQR. E) Quantification of AQR and PQR defects. The table indicates the positions of AQR and PQR in wild-type and ptpn-22 mutants. The figure above the table shows the five positions along the anterior-posterior axis of the animal that were used to score AQR and PQR position. For each genotype, 100 animals were scored. The asterisks indicate that the AQR defects in the mutants were significantly less severe than those in ptpn-22(fd388) and ptpn-22(fd406) (p < 0.03).
","imageTitle":"ptpn-22 mutants displays AQR and PQR migration defects
","methods":"C. elegans strains were maintained and scored at 20°C. AQR and PQR were visualized using the Pgcy-32::cfp transgene lqIs244 (Chapman et al., 2008; Josephson et al., 2016) (Chapman et al. 2008; Josephson et al. 2016). AQR and PQR positions along the body were noted using a five-position scale as previously described (Jain et al., 2026; Jain & Lundquist, 2025; Josephson et al., 2016) (See Fig 1E). Statistical significance was determined using Fisher's Exact test.
","reagents":"The following C. elegans mutants and transgenes were used: LGII, lqIs244[Pgcy-32::cfp]; LGIV, ptpn-22(gk194708), ptpn-22(gk3186), ptpn-22(fd331), ptpn-22(fd388), ptpn-22(fd406). The tmC25 balancer 27 was used to isolate ptpn-22 mutant chromosomes. The presence of ptpn-22 mutations was confirmed by sequencing or PCR genotyping. The following strains were analyzed:
Strain | Genotype | Origin |
lqIs244 II | (Josephson et al., 2016) | |
(Binti et al., 2024) and this work | ||
(Binti et al., 2024) and this work | ||
(Binti et al., 2024) and this work | ||
(Binti et al., 2024) and this work | ||
(Binti et al., 2024) and this work |
C. elegans PTPN-22 is an ortholog of the vertebrate protein tyrosine phosphatase non-receptor type 22 PTPN22 (Begovich et al., 2004; Binti et al., 2024; Cohen et al., 1999). PTPN22 has been investigated in mammalian systems for its roles in lymphoid and immune function (Bottini & Peterson, 2014; Cohen et al., 1999; Hill et al., 2002), notably suppression of T cell activation (Cloutier & Veillette, 1999) and viral immunity (Bevis et al., 2026; Orozco et al., 2024). In human populations, Ptpn22 variants are associated with autoimmune disorders (Armitage et al., 2021; Gregersen et al., 2012). In humans, Ptpn22 is expressed strongly in lymphoid tissues, with lower expression in other tissue types (Thul et al., 2017; Uhlen et al., 2015). In C. elegans, mutations in ptpn-22 have been shown to suppress cuticular molting defects due to mutations in NIMA-like kinases NEKL-2 and NEKL-3, and to be associated with hypodermal adhesion complexes including hemidesmosomes (Binti et al., 2024).
Single-cell RNA sequencing of the Q neuroblast lineage shows that ptpn-22 is expressed throughout the Q neuroblast lineages as they develop (Figure 1A and B) (Teixeira et al., 2026). The bilateral Q neuroblasts, are derived embryonically and migrate in the L1 larva after hatching (Chapman et al., 2008; Middelkoop & Korswagen, 2014; Rella et al., 2016; Schild et al., 2023; Sulston & Horvitz, 1977). QR on the right migrates anteriorly over the V4 seam cell, and QL on the left migrates posteriorly over the V5 seam cell (Chapman et al., 2008). A similar pattern of cell division, programmed cell death, and neuronal differentiation results in three neurons on each side: AQR, AVM, and SDQR on the right, and PQR, PVM, and SDQL on the left. The QR descendant AQR migrate farthest anteriorly to the deirid ganglion near the pharynx (Figure 1C). The QL descendant PQR migrates the farthest posteriorly to the phasmid ganglion posterior to the anus (Figure 1C). Mutations that disrupt Q lineage migrations result in misplaced AQR and/or PQR neurons. Directional defects in migration (e.g. anterior PQR migration or posterior AQR migration) result from mutations that affect the first Q cell migration and subsequent Wnt-mediated activation of the Hox transcription factor MAB-5/Antennapedia (Josephson et al., 2016). Failure of migration (e.g. AQR and PQR migrate in the correct direction but do not complete migration) can result from disruption of the migration substrate such as epi-1/Laminin-α5 mutation (Lang & Lundquist, 2021), or from mutation of downstream target genes of MAB-5/Antennapedia (Jain et al., 2026; Jain & Lundquist, 2025).
We analyzed AQR and PQR migration in five ptpn-22 alleles (Binti et al., 2024). All five alleles showed failure of complete AQR migration (9-33%) (Figure 1D and E). PQR migration failure was noted in three of the five mutants (0-6%) (Figure 1D and E). No directional migration defects were noted. Rather, AQR and PQR migrated in the correct direction but failed complete migration. Misplaced AQR were displaced posteriorly behind the pharynx, and misplaced PQR were displaced anteriorly, immediately anterior to the anus (Figure 1D). This phenotype is consistent with failure of the third migration of QL.ap/PQR posterior to the anus (Jain et al., 2026; Jain & Lundquist, 2025), and might also represent a late-stage failure of QR.ap/AQR migration (Middelkoop & Korswagen, 2014; Rella et al., 2016). ptpn-22(fd388) introduces a premature stop codon in the second codon exon, and ptpn-22(fd406) is a cysteine to serine missense mutation in the phosphatase catalytic domain (Binti et al., 2024). These two mutants displayed significantly stronger AQR migration defects compared to the other three alleles analyzed (fd331, a frameshift; gk3186, a deletion of the first two coding exons; and gk194708, a premature stop codon in the second to last codon exon) (Binti et al., 2024; Thompson et al., 2013). Each of these is predicted to be a complete loss-of-function, and it is unclear why they have a significantly weaker phenotype than ptpn-22(fd388). This could be due to the genetic background of ptpn-22(fd388), or to retention of some function in fd331, gk3186, and gk194708. The catalytically-dead ptpn-22(fd406) could be significantly stronger because of a potential dominant-negative function (i.e. the molecule might interact with binding partners leading to a non-functional complex). In sum, these results indicate that PTPN-22 is required for migration of the AQR and PQR neurons and defines a new function of the Ptpn22 family. While ptpn-22 expression in the Q lineage is likely not controlled by MAB-5/Antennapedia (Paolillo et al., 2024), the evidence here could suggest that PTPN-22 is required for the ability of AQR and PQR to migrate fully.
A balance of tyrosine phosphorylation and dephosphorylation is important in QR lineage migrations (Zhu et al., 2020): the SRC-1/Src tyrosine kinase phosphorylates the guidance receptor MIG-13 to regulate actin polymerization in the direction of migration, and the receptor tyrosine phosphatase PTP-3/LAR is responsible for mitigating this in the rear of the migrating cells. Src kinases are key substrates for PTPN22 activity in the immune system (Cloutier & Veillette, 1999; Wu et al., 2006). It is possible that PTPN-22 participates in this tyrosine phosphorylation balance underlying AQR and PQR migration via modulating cytoskeletal or cell adhesion functions. In any case, these results are consistent with an ancestral role of PTPN22 family members in regulating cell adhesion and migration.
","references":[{"reference":"Armitage LH, Wallet MA, Mathews CE. 2021. Influence of PTPN22 Allotypes on Innate and Adaptive Immune Function in Health and Disease. Front Immunol. 12: 636618. 4611.","pubmedId":"33717184","doi":"10.3389/fimmu.2021.636618"},{"reference":"Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP, Alexander HC, et al., Gregersen PK. 2004. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet. 75: 330-7. 4604.","pubmedId":"15208781","doi":"10.1086/422827"},{"reference":"Bevis AM, Rosa K, Schwarting N, Cockerham TR, Kerr CM, More S, Fehr AR, Orozco RC. 2026. An autoimmunity-associated allele of PTPN22 enhances innate antiviral immunity to protect against acute coronavirus infection. Proc Natl Acad Sci U S A. 123: e2519903123. 4608.","pubmedId":"41849391","doi":"10.1073/pnas.2519903123"},{"reference":"Binti S, Linder AG, Edeen PT, Fay DS. 2024. 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