Protein Tyrosine Phosphatase δ Mediates the Sema3A-Induced Cortical Basal Dendritic Arborization through the Activation of Fyn Tyrosine Kinase

J Neurosci. 2017 Jul 26;37(30):7125-7139. doi: 10.1523/JNEUROSCI.2519-16.2017. Epub 2017 Jun 21.

Abstract

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

Keywords: C. elegans; Fyn; LAR; PTP-3; PTPRD; PTPδ; Sema2A; Sema3A; dendritic growth; pyramidal neuron.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Cerebral Cortex / physiology*
  • Cerebral Cortex / ultrastructure
  • Dendrites / physiology*
  • Dendrites / ultrastructure
  • Enzyme Activation
  • Female
  • Gene Expression Regulation, Enzymologic / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Neuronal Plasticity / physiology*
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins c-fyn / metabolism*
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2 / metabolism*
  • Semaphorin-3A / metabolism*

Substances

  • Sema3a protein, mouse
  • Semaphorin-3A
  • Protein-Tyrosine Kinases
  • Fyn protein, mouse
  • Proto-Oncogene Proteins c-fyn
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2