Open AccessNeuritic complexity of hippocampal neurons depends on WIP ‐mediated mTORC 1 and Abl family kinases activities
Author(s) -
FrancoVillanueva Ana,
Wandosell Francisco,
Antón Inés M.
Publication year - 2015
Publication title -
brain and behavior
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.915
H-Index - 41
ISSN - 2162-3279
DOI - 10.1002/brb3.359
Subject(s) - microbiology and biotechnology , biology , p70 s6 kinase 1 , phosphorylation , kinase , mtorc1 , signal transduction , ribosomal s6 kinase , pi3k/akt/mtor pathway
Abstract Introduction 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 ( mTORC 1)‐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 ( PI 3K)‐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 mTORC 1 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. Conclusion These experiments identify WIP as a member of a signaling cascade comprised of Abl family kinases, mTORC 1 and S6K, which regulates neuron development and specifically, neuritic branching and complexity. Thus, we postulated a new role for WIP protein.