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The actin\u2010binding molecule <jats:styled-content style=\"fixed-case\">WIP<\/jats:styled-content> (Wiskott\u2010Aldrich syndrome protein [<jats:styled-content style=\"fixed-case\">WASP<\/jats:styled-content>]\u2010interacting protein) was identified as a negative regulator of neuritogenesis. Although <jats:styled-content style=\"fixed-case\">WIP<\/jats:styled-content> controls activity of the actin\u2010nucleation\u2010promoting factor neural <jats:styled-content style=\"fixed-case\">WASP<\/jats:styled-content> (N\u2010<jats:styled-content style=\"fixed-case\">WASP<\/jats:styled-content>) during neuritic differentiation, its implication in signal transduction remains unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Using primary neurons from <jats:styled-content style=\"fixed-case\">WIP<\/jats:styled-content>\u2010deficient and wild\u2010type mice we did an immunofluorescence, morphometric, and biochemical analysis of the signaling modified by <jats:styled-content style=\"fixed-case\">WIP<\/jats:styled-content> deficiency.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Here, we describe the <jats:styled-content style=\"fixed-case\">WIP<\/jats:styled-content> 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 (<jats:styled-content style=\"fixed-case\">mTORC<\/jats:styled-content>1)\u2010p70S6K (phosphoprotein 70 ribosomal protein S6 kinase, S6K) intracellular signaling pathway. <jats:styled-content style=\"fixed-case\">WIP<\/jats:styled-content> 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 (<jats:styled-content style=\"fixed-case\">PI<\/jats:styled-content>3K)\u2010Akt pathway, but to reduced phosphorylation of the S6K residues Ser<jats:sup>411<\/jats:sup> and Thr<jats:sup>389<\/jats:sup>. The resulting decrease in kinase activity leads to reduced S6 phosphorylation in the absence of <jats:styled-content style=\"fixed-case\">WIP<\/jats:styled-content>. Incubation of control neurons with pharmacological inhibitors of <jats:styled-content style=\"fixed-case\">mTORC<\/jats:styled-content>1 or Abl, two S6K regulators, conferred a morphology resembling that of <jats:styled-content style=\"fixed-case\">WIP<\/jats:styled-content>\u2010deficient neurons. Moreover, the preferential co\u2010distribution of phospho\u2010S6K with polymerized actin is altered in <jats:styled-content style=\"fixed-case\">WIP<\/jats:styled-content>\u2010deficient neurons.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These experiments identify <jats:styled-content style=\"fixed-case\">WIP<\/jats:styled-content> as a member of a signaling cascade comprised of Abl family kinases, <jats:styled-content style=\"fixed-case\">mTORC<\/jats:styled-content>1 and S6K, which regulates neuron development and specifically, neuritic branching and complexity. Thus, we postulated a new role for <jats:styled-content style=\"fixed-case\">WIP<\/jats:styled-content> protein.<\/jats:p><\/jats:sec>","DOI":"10.1002\/brb3.359","type":"journal-article","created":{"date-parts":[[2015,10,4]],"date-time":"2015-10-04T05:04:41Z","timestamp":1443935081000},"source":"Crossref","is-referenced-by-count":5,"title":["Neuritic complexity of hippocampal neurons depends on <scp>WIP<\/scp>\u2010mediated <scp>mTORC<\/scp>1 and Abl family kinases activities"],"prefix":"10.1002","volume":"5","author":[{"given":"Ana","family":"Franco\u2010Villanueva","sequence":"first","affiliation":[{"name":"Centro Nacional de Biotecnolog\u00eda (CNB\u2010CSIC) Darwin 3 Campus Cantoblanco 28049 Madrid Spain"},{"name":"CIBERNED, Centro Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Neurodegenerativas Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Wandosell","sequence":"additional","affiliation":[{"name":"CIBERNED, Centro 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