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Sprouty2 inhibits BDNF-induced signaling and modulates neuronal differentiation and survival
I Gross1, O Armant, S Benosman
1U682 INSERM, 3 avenue Molière, Strasbourg 67200, France. isabelle.gross@inserm.u-strasbg.fr
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.
Insights
Sprouty 2 (Spry2) inhibits neuronal differentiation and survival in the central nervous system (CNS). Brain-derived neurotrophic factor (BDNF) regulates Spry2, impacting neurite formation and neuronal cell death.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Sprouty (Spry) proteins regulate receptor tyrosine kinase signaling pathways.
- These pathways are crucial for cell proliferation, differentiation, and survival.
- The role of Spry2 in the central nervous system (CNS) requires further investigation.
Purpose of the Study:
- To investigate the regulation of Spry2 expression in CNS cells.
- To elucidate the role of Spry2 in neuronal differentiation and survival.
- To identify regulatory factors of Spry2 in response to neurotrophic factors.
Main Methods:
- Primary neuronal cultures (immature and mature).
- Analysis of spry2 promoter activity using transcription factors CREB and SP1.
- Manipulation of Spry2 levels via overexpression and inhibition (dominant-negative mutant, siRNA).
- Assessment of neurite formation, neurofilament light chain expression, and neuronal apoptosis.
Main Results:
- Brain-derived neurotrophic factor (BDNF) regulates spry2 expression in immature neurons.
- CREB and SP1 are key regulators of BDNF-induced spry2 promoter activation.
- Spry2 overexpression inhibits neurite formation and neurofilament light chain expression in immature neurons.
- Spry2 inhibition promotes neurite sprouting.
- Spry2 expression is sustained by BDNF in mature neurons and downregulated during apoptosis.
- Spry2 overexpression induces neuronal cell death, while inhibition promotes survival in mature neurons.
Conclusions:
- Spry2 plays a critical role in CNS development by inhibiting neuronal differentiation and survival.
- Spry2 acts via a negative-feedback loop, downregulating neurotrophic factor signaling pathways.
- Understanding Spry2 regulation is vital for targeting CNS developmental processes and neuronal health.
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