Description
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.