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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...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2015
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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. |
format | Online Article Text |
id | pubmed-4667760 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
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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