title: Neuritic complexity of hippocampal neurons depends on WIP-mediated mTORC1 and Abl family kinases activities.
abstract: BACKGROUND
  Neuronal morphogenesis is governed mainly by two interconnected processes, cytoskeletal reorganization, and signal transduction. The actin-binding molecule WIP (Wiskott-Aldrich syndrome protein [WASP]-interacting protein) was identified as a negative regulator of neuritogenesis. Although WIP controls activity of the actin-nucleation-promoting factor neural WASP (N-WASP) during neuritic differentiation, its implication in signal transduction remains unknown.
  
  
  METHODS
  Using primary neurons from WIP-deficient and wild-type mice we did an immunofluorescence, morphometric, and biochemical analysis of the signaling modified by WIP deficiency.
  
  
  RESULTS
  Here, we describe the WIP contribution to the regulation of neuritic elaboration and ramification through modification in phosphorylation levels of several kinases that participate in the mammalian target of rapamycin complex 1 (mTORC1)-p70S6K (phosphoprotein 70 ribosomal protein S6 kinase, S6K) intracellular signaling pathway. WIP deficiency induces an increase in the number of neuritic bifurcations and filopodial protrusions in primary embryonic neurons. This phenotype is not due to modifications in the activity of the phosphoinositide 3 kinase (PI3K)-Akt pathway, but to reduced phosphorylation of the S6K residues Ser(411) and Thr(389). The resulting decrease in kinase activity leads to reduced S6 phosphorylation in the absence of WIP. Incubation of control neurons with pharmacological inhibitors of mTORC1 or Abl, two S6K regulators, conferred a morphology resembling that of WIP-deficient neurons. Moreover, the preferential co-distribution of phospho-S6K with polymerized actin is altered in WIP-deficient neurons.
  
  
  CONCLUSIONS
  These experiments identify WIP as a member of a signaling cascade comprised of Abl family kinases, mTORC1 and S6K, which regulates neuron development and specifically, neuritic branching and complexity. Thus, we postulated a new role for WIP protein.
authors.affiliation: Centro Nacional de Biotecnología (CNB-CSIC) Darwin 3 Campus Cantoblanco 28049 Madrid Spain ; CIBERNED, Centro Investigación Biomédica en Red de Enfermedades Neurodegenerativas Madrid Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Franco-Villanueva
authors.affiliation: CIBERNED, Centro Investigación Biomédica en Red de Enfermedades Neurodegenerativas Madrid Spain ; Centro de Biología Molecular Severo Ochoa (CBMSO) (CSIC-UAM) Nicolás Cabrera 1 Campus Cantoblanco 28049 Madrid Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Wandosell
authors.affiliation: Centro Nacional de Biotecnología (CNB-CSIC) Darwin 3 Campus Cantoblanco 28049 Madrid Spain ; CIBERNED, Centro Investigación Biomédica en Red de Enfermedades Neurodegenerativas Madrid Spain.
authors.forename: Inés M
authors.initials: IM
authors.lastname: Antón
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008815:Mice, Inbred Strains; D046912:Multiprotein Complexes / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014923:Wiskott-Aldrich Syndrome / Q000378:metabolism
chemical_list: D000199:Actins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D016315:Proto-Oncogene Proteins c-abl; D058570:TOR Serine-Threonine Kinases; C491671:Waspip protein, mouse
keywords: Abl; S6K; branching; mammalian target of rapamycin complex; neuritogenesis