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Sprouty2 inhibits BDNF signalling

Sprouty2 inhibits BDNF signalling - Cell Death and...

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Sprouty2 inhibits BDNF-induced signaling and modulates neuronal differentiation and survival I Gross* ,1 , O Armant 2 , S Benosman 3 , JLG de Aguilar 3 , J-N Freund 1 , M Kedinger 1 , JD Licht 4 , C Gaiddon* ,3 and J-P Loeffler 3 Sprouty (Spry) proteins are ligand-inducible inhibitors of receptor tyrosine kinases-dependent signaling pathways, which control various biological processes, including proliferation, differentiation and survival. Here, we investigated the regulation and the role of Spry2 in cells of the central nervous system (CNS). In primary cultures of immature neurons, the neurotrophic factor BDNF (brain-derived neurotrophic factor) regulates spry2 expression. We identified the transcription factors CREB and SP1 as important regulators of the BDNF activation of the spry2 promoter. In immature neurons, we show that overexpression of wild- type Spry2 blocks neurite formation and neurofilament light chain expression, whereas inhibition of Spry2 by a dominant- negative mutant or small interfering RNA favors sprouting of multiple neurites. In mature neurons that exhibit an extensive neurite network, spry2 expression is sustained by BDNF and is downregulated during neuronal apoptosis. Interestingly, in these differentiated neurons, overexpression of Spry2 induces neuronal cell death, whereas its inhibition favors neuronal survival. Together, our results imply that Spry2 is involved in the development of the CNS by inhibiting both neuronal differentiation and survival through a negative-feedback loop that downregulates neurotrophic factors-driven signaling pathways. Cell Death and Differentiation (2007) 14, 1802–1812; doi:10.1038/sj.cdd.4402188; published online 29 June 2007 The neurotrophin BDNF (brain-derived neurotrophic factor) is widely expressed in the mammalian central nervous system (CNS) and plays a key role in its development and homeo- stasis. 1 At the cellular level, BDNF induces neuronal differentiation and neurite outgrowth, 2 facilitates plasticity, 3 and favors neuronal survival. 4 BDNF binds to the tyrosine kinase receptor TrkB, which activates at least three signal transduction pathways: (i) the Ras/mitogen-activated protein (MAP) kinase (Ras/MAPK) pathway; (ii) the PI3-Kinase/Akt pathway; and (iii) the PLC g pathway. 5 Activation of these pathways allows BDNF to regulate transcription 6 and ulti- mately accounts for its role in neuronal differentiation and survival. 2 The coordinated action of extracellular signals that lead to brain development and maintenance requires a tight spatial and temporal control, which is partly achieved by negative- feedback loops, involving the clearance of the receptor, the phosphorylation state of proteins, or the expression of counteracting factors. 7 Over the past few years, members of the Sprouty (Spry) family of proteins have emerged as critical modulators of growth factor signaling (for recent reviews, see Mason et al .
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