This is the first evidence showing that LAR class PTPs participate in Semaphorin signaling in vivo. In Sema3A signaling, PTPδ activates Fyn and Src kinases by dephosphorylating their C-terminal Tyr residues. PTPδ, a member of vertebrate LAR class PTPs, is involved in Sema3A-regulated cortical dendritic growth. We show that PTP-3, a LAR homolog in Caenorhabditis elegans, participates in Sema2A-regulated axon guidance. SIGNIFICANCE STATEMENT The relation of leukocyte common antigen-related (LAR) class protein tyrosine phosphatases (PTPs) and specific axon guidance cues is poorly defined. Collectively, PTPδ mediates Sema3A-signaling through the activation of Fyn by C-terminal dephosphorylation. Arborization of cortical basal dendrites was reduced in Fyn −/− as well as in Ptpδ +/− Fyn +/− double-heterozygous mutants. Sema3A-stimulation induced dephosphorylation of Tyr527 in the dendrites of wild-type cortical neurons but not of Ptpδ −/−. In Ptpδ −/− brains, Fyn and Src kinases were hyperphosphorylated at their C-terminal Tyr527 residues. The double-heterozygous mutants, Ptpδ +/− Sema3a +/−, also showed a similar phenotype, indicating the genetic interaction. This phenotype was observed in both male and female mutants. Ptpδ −/− and Sema3a −/− mutant mice exhibited poor arborization of basal dendrites of cortical layer V neurons. Instead, PTPδ played a major role in Sema3A-dependent cortical dendritic growth. In vivo, however, the contribution of PTPδ in Sema3A-regualted axon guidance was minimal. PTPδ, one of the vertebrate LAR class PTPs, participates in the Semaphorin-3A (Sema3A)-induced growth cone collapse response of primary cultured dorsal root ganglion neurons from Mus musculus embryos. We here show that PTP-3, a LAR homolog in Caenorhabditis elegans, is involved in axon guidance regulated by Semaphorin-2A-signaling. Leukocyte common antigen-related (LAR) class protein tyrosine phosphatases (PTPs) are critical for axonal guidance however, their relation to specific guidance cues is poorly defined.
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