title: CD47 promotes neuronal development through Src- and FRG/Vav2-mediated activation of Rac and Cdc42.
abstract: The development of axons and dendrites is controlled by small GTP-binding proteins of the Rho family, but the upstream signaling mechanisms responsible for such regulation remain unclear. We have now investigated the role of the transmembrane protein cluster of differentiation 47 (CD47) in this process with hippocampal neurons. CD47-deficient neurons manifested markedly impaired development of dendrites and axons, whereas overexpression of CD47 promoted such development. Interaction of SH2 domain-containing protein tyrosine phosphatase substrate-1 (SHPS-1) with CD47 also induced the formation of dendritic filopodia and spines. These effects of CD47 were prevented by inhibition of either cell division cycle 42 (Cdc42) or Rac. In CD47-deficient neurons, autophosphorylation of Src was markedly reduced. In addition, overexpression of CD47 promoted the autophosphorylation of Src. Inhibition of Src family kinases indeed prevented CD47-promoted dendritic development. Inhibition of either FGD1-related Cdc42-guanine nucleotide exchange factor (GEF) (FRG) or Vav2, which is a GEF for Cdc42 and Rac and is activated by Src, also prevented the effects of CD47 on dendritic development. These results indicate that CD47 promotes development of dendrites and axons in hippocampal neurons in a manner dependent, at least in part, on activation of Cdc42 and Rac mediated by Src as well as by FRG and Vav2.
authors.affiliation: Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma 371-8512, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Murata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohnishi
authors.forename: Hideki
authors.initials: H
authors.lastname: Okazawa
authors.forename: Yoji
authors.initials: Y
authors.lastname: Murata
authors.forename: Shinya
authors.initials: S
authors.lastname: Kusakari
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Motoaki
authors.initials: M
authors.lastname: Miyashita
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
authors.forename: Per-Arne
authors.initials: PA
authors.lastname: Oldenborg
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Furuya
authors.forename: Takashi
authors.initials: T
authors.lastname: Matozaki
mesh_terms: D000818:Animals; D051928:CD47 Antigen / Q000378:metabolism*; D002478:Cells, Cultured; D020662:Guanine Nucleotide Exchange Factors; D006624:Hippocampus / Q000254:growth & development / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology* / Q000378:metabolism* / Q000502:physiology; D011506:Proteins / Q000502:physiology*; D051567:Proto-Oncogene Proteins c-vav / Q000502:physiology*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D019061:src-Family Kinases / Q000502:physiology*
chemical_list: D051928:CD47 Antigen; C497895:Cd47 protein, mouse; C097489:Fgd1 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D011506:Proteins; D051567:Proto-Oncogene Proteins c-vav; C490565:Vav2 protein, mouse; D019061:src-Family Kinases; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins