Original Paper
Cell Death and Differentiation (2007) 14, 1802–1812; doi:10.1038/sj.cdd.4402188; published online 29 June 2007
Sprouty2 inhibits BDNF-induced signaling and modulates neuronal differentiation and survival
Edited by N Bazan
I Gross1, O Armant2, S Benosman3, J L G de Aguilar3, J-N Freund1, M Kedinger1, J D Licht4, C Gaiddon3 and J-P Loeffler3
- 1U682 INSERM, Strasbourg, France
- 2Institute of Toxicology and Genetics, Forschungszentrum, Karlsruhe, D-76021, Germany
- 3U692 INSERM, Université Louis Pasteur, Faculté de Médecine, Strasbourg, France
- 4Northwestern University Feinberg School of Medicine, Chicago, IL, USA
Correspondence: I Gross, U682 INSERM, 3 av. Molière, Strasbourg 67200, France. Tel: +33 388275367; Fax: +33 388263538; E-mail: isabelle.gross@inserm.u-strasbg.fr; C Gaiddon, U692 INSERM, Université Louis Pasteur, Faculté de Médecine, Strasbourg, France. E-mail: gaiddon@neurochem.u-strasbg.fr
Received 30 January 2007; Revised 26 April 2007; Accepted 4 May 2007; Published online 29 June 2007.
Abstract
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.
Keywords:
sprouty, neuron, neurite growth, apoptosis, CREB, SP1
Abbreviations:
APP, amyloid beta precursor protein; BDNF, brain derived neurotrophic factor; CGN, cerebellar granule neurons; CMV, cytomegalovirus; CNS, central nervous system; dig, digoxigenin; DMEM, Dulbecco's modified Eagle's medium; E, embryonic day; EGL, external granule cell layer; FGF, fibroblast growth factor; GDNF, glial cell derived neurotrophic factor; GFP, green fluorescent protein; HK, high potassium; ISH, in situ hybridization; LHC, L-homo-cystein; LK, low potassium; Luc, luciferase; MAPK, mitogen-activated protein kinase; NFLC, neurofilament light chain; PAF, paraformaldehyde; PBS, phosphate-buffered saline; PEI, polyethyleneimine; RTK, receptor tyrosine kinase; RT-qPCR, reverse transcription-quantitative polymerase chain reaction; siRNA, small interfering RNA; YFP, yellow fluorescent protein
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