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

Brain and Behavior

Ana Franco-Villanueva²  Francisco Wandosell¹ 

[1] CIBERNED, Centro Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Madrid, Spain;Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain

关键词: Abl;    branching;    mammalian target of rapamycin complex;    neuritogenesis;    S6K;   

DOI  :  10.1002/brb3.359

来源: Wiley

【 摘 要 】

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 (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 Ser⁴¹¹ and Thr³⁸⁹. 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.

【 授权许可】

CC BY   
© 2015 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.

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