title: A short splicing isoform of afadin suppresses the cortical axon branching in a dominant-negative manner.
abstract: Precise wiring patterns of axons are among the remarkable features of neuronal circuit formation, and establishment of the proper neuronal network requires control of outgrowth, branching, and guidance of axons. R-Ras is a Ras-family small GTPase that has essential roles in multiple phases of axonal development. We recently identified afadin, an F-actin-binding protein, as an effector of R-Ras mediating axon branching through F-actin reorganization. Afadin comprises two isoforms--l-afadin, having the F-actin-binding domain, and s-afadin, lacking the F-actin-binding domain. Compared with l-afadin, s-afadin, the short splicing variant of l-afadin, contains RA domains but lacks the F-actin-binding domain. Neurons express both isoforms; however, the function of s-afadin in brain remains unknown. Here we identify s-afadin as an endogenous inhibitor of cortical axon branching. In contrast to the abundant and constant expression of l-afadin throughout neuronal development, the expression of s-afadin is relatively low when cortical axons branch actively. Ectopic expression and knockdown of s-afadin suppress and promote branching, respectively. s-Afadin blocks the R-Ras-mediated membrane translocation of l-afadin and axon branching by inhibiting the binding of l-afadin to R-Ras. Thus s-afadin acts as a dominant-negative isoform in R-Ras-afadin-regulated axon branching.
authors: Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Kentaro
authors: K
authors: Umeda
authors: Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Nariaki
authors: N
authors: Iwasawa
authors: Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Manabu
authors: M
authors: Negishi
authors: Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan PRESTO, Japan Science and Technology Agency, 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan izu-oinuma@lif.kyoto-u.ac.jp.
authors: Izumi
authors: I
authors: Oinuma
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000502:physiology*; D002540:Cerebral Cortex / Q000378:metabolism / Q000502:physiology*; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000502:physiology*; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D051381:Rats; D018631:ras Proteins / Q000378:metabolism
chemical_list: D008840:Microfilament Proteins; D020033:Protein Isoforms; C108835:afadin; D018631:ras Proteins