The death receptor antagonist FLIP-L interacts with Trk and is necessary for neurite outgrowth induced by neurotrophins

Moubarak, Rana S and Solé, Carme and Pascual, Marta and Gutierrez, Humberto and Llovera, Marta and Pérez-García, M José and Gozzelino, Raffaella and Segura, Miguel F. and Iglesias-Guimarais, Victoria and Reix, Stéphanie and Soler, Rosa M. and Davies, Alun M. and Soriano, Eduardo and Yuste, Victor J. and Comella, Joan X. (2010) The death receptor antagonist FLIP-L interacts with Trk and is necessary for neurite outgrowth induced by neurotrophins. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 30 (17). pp. 6094-9105. ISSN UNSPECIFIED

Full content URL: http://dx.doi.org/10.1523/JNEUROSCI.0537-10.2010

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Item Type:Article
Item Status:Live Archive

Abstract

FLICE-inhibitory protein (FLIP) is an endogenous inhibitor of the signaling pathway triggered by the activation of death receptors. Here, we reveal a novel biological function for the long form of FLIP (FLIP-L) in neuronal differentiation, which can be dissociated from its antiapoptotic role. We show that FLIP-L is expressed in different regions of the mouse embryonic nervous system. Immunohistochemistry of mouse brain sections at different stages reveals that, in neurons, FLIP is expressed early during the embryonic neuronal development (embryonic day 16) and decreases at later stages (postnatal days 5-15), when its expression is essentially detected in glial cells. FLIP-L overexpression significantly enhances neurotrophin-induced neurite outgrowth in motoneurons, superior cervical ganglion neurons, and PC12 cells. Conversely, the downregulation of FLIP-L protein levels by specific RNA interference significantly reduces neurite outgrowth, even in the presence of the appropriate neurotrophin stimulus. Moreover, NGF-dependent activation of two main intracellular pathways involved in the regulation of neurite outgrowth, extracellular signal-regulated kinases (ERKs) and nuclear factor kappaB (NF-kappaB), is impaired when endogenous FLIP-L is downregulated, although TrkA remains activated. Finally, we demonstrate that FLIP-L interacts with TrkA, and not with p75(NTR), in an NGF-dependent manner, and endogenous FLIP-L interacts with TrkB in whole-brain lysates from embryonic day 15 mice embryos. Altogether, we uncover a new role for FLIP-L as an unexpected critical player in neurotrophin-induced mitogen-activated protein kinase/ERK- and NF-kappaB-mediated control of neurite growth in developing neurons.

Keywords:Neuronal Development
Subjects:C Biological Sciences > C141 Developmental Biology
Divisions:College of Science > School of Life Sciences
ID Code:7854
Deposited On:21 Mar 2013 11:30

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