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

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

Author information

1
Department of Molecular Pharmacology and Neurobiology, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa 236-0004, Japan, f-nakamura@umin.ac.jp stephen.strittmatter@yale.edu.
2
Departments of Neurology and of Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06536.
3
Department of Biochemistry, School of Medicine, Tokyo Women's Medical University, Tokyo, 162-8666, Japan.
4
Department of Molecular Pharmacology and Neurobiology, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa 236-0004, Japan.
5
Department of Neuroscience, Johns Hopkins University, Baltimore, Maryland 21218.
6
Goodman Cancer Centre, McGill University, Montreal, Quebec, H3G 1Y6, Canada.
7
Department of Biochemistry, Cancer Research Institute, Sapporo Medical University, Sapporo 060-8556, Japan.
8
KOKORO-Biology Group, Laboratories for Integrated Biology, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan.
9
Division of Experimental Animal Immunology, Research Institute for Biomedical Science, Tokyo University of Science, Noda, Chiba 278-0022, Japan.
10
Laboratory for Molecular Brain Science, Department of Life Science and Medical Bio-science, Waseda University, Tokyo, 162-8480, Japan, and.
11
Departments of Neurology and of Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06536, f-nakamura@umin.ac.jp stephen.strittmatter@yale.edu.

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

PMID:
28637841
DOI:
10.1523/JNEUROSCI.2519-16.2017
[Indexed for MEDLINE]
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