Sprouty2 inhibits BDNF-induced signaling and modulates neuronal differentiation and survival.
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.
Gross
I
I
U682 INSERM, 3 avenue Molière, Strasbourg 67200, France. isabelle.gross@inserm.u-strasbg.fr
Armant
O
O
Benosman
S
S
de Aguilar
J L G
JL
Freund
J-N
JN
Kedinger
M
M
Licht
J D
JD
Gaiddon
C
C
Loeffler
J-P
JP
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D019208:Brain-Derived Neurotrophic Factor; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D016329:Sp1 Transcription Factor; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C118389:Spry2 protein, mouse