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Neuritic complexity of hippocampal neurons depends on WIP‐mediated mTORC1 and Abl family kinases activities

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. Althou...

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Autores principales: Franco‐Villanueva, Ana, Wandosell, Francisco, Antón, Inés M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667760/
https://www.ncbi.nlm.nih.gov/pubmed/26664784
http://dx.doi.org/10.1002/brb3.359
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author Franco‐Villanueva, Ana
Wandosell, Francisco
Antón, Inés M.
author_facet Franco‐Villanueva, Ana
Wandosell, Francisco
Antón, Inés M.
author_sort Franco‐Villanueva, Ana
collection PubMed
description 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 (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. CONCLUSION: 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.
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spelling pubmed-46677602015-12-10 Neuritic complexity of hippocampal neurons depends on WIP‐mediated mTORC1 and Abl family kinases activities Franco‐Villanueva, Ana Wandosell, Francisco Antón, Inés M. Brain Behav Original Research 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 (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. CONCLUSION: 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. John Wiley and Sons Inc. 2015-10-03 /pmc/articles/PMC4667760/ /pubmed/26664784 http://dx.doi.org/10.1002/brb3.359 Text en © 2015 The Authors. Brain and Behavior published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Research
Franco‐Villanueva, Ana
Wandosell, Francisco
Antón, Inés M.
Neuritic complexity of hippocampal neurons depends on WIP‐mediated mTORC1 and Abl family kinases activities
title Neuritic complexity of hippocampal neurons depends on WIP‐mediated mTORC1 and Abl family kinases activities
title_full Neuritic complexity of hippocampal neurons depends on WIP‐mediated mTORC1 and Abl family kinases activities
title_fullStr Neuritic complexity of hippocampal neurons depends on WIP‐mediated mTORC1 and Abl family kinases activities
title_full_unstemmed Neuritic complexity of hippocampal neurons depends on WIP‐mediated mTORC1 and Abl family kinases activities
title_short Neuritic complexity of hippocampal neurons depends on WIP‐mediated mTORC1 and Abl family kinases activities
title_sort neuritic complexity of hippocampal neurons depends on wip‐mediated mtorc1 and abl family kinases activities
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667760/
https://www.ncbi.nlm.nih.gov/pubmed/26664784
http://dx.doi.org/10.1002/brb3.359
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AT antoninesm neuriticcomplexityofhippocampalneuronsdependsonwipmediatedmtorc1andablfamilykinasesactivities