Sprouty2 inhibits BDNF-induced signaling and modulates neuronal differentiation and survival
Sprouty2 inhibits BDNF-induced signaling and modulates neuronal differentiation and survival
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DOI：
10.1038/sj.cdd.4402188
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发表时间：
2007-10-01
影响因子：
12.4
通讯作者：
Loeffler, J-P
中科院分区：
文献类型：
--
作者：
Gross, I.;Armant, O.;Loeffler, J-P
Sprouty（Spry）蛋白是受体酪氨酸激酶依赖的信号通路的配体诱导抑制剂，其控制各种生物过程，包括增殖、分化和存活。在这里，我们研究了Spry2在中枢神经系统（CNS）细胞中的调节和作用。在未成熟神经元的原代培养物中，神经营养因子BDNF（脑源性神经营养因子）调节spry 2表达。我们确定了转录因子CREB和SP1作为BDNF激活spry2启动子的重要调节因子。在未成熟的神经元中，我们发现野生型Spry2的过表达阻断了神经突的形成和神经丝轻链的表达，而显性负突变体或小干扰RNA对Spry2的抑制有利于多个神经突的发芽。在表现出广泛的神经突网络的成熟神经元中，spry 2表达由BDNF维持，并且在神经元凋亡期间下调。有趣的是，在这些分化的神经元中，Spry2的过表达诱导神经元细胞死亡，而其抑制有利于神经元存活。总之，我们的研究结果表明，Spry2通过抑制神经元分化和存活，通过负反馈回路，下调神经营养因子驱动的信号通路参与CNS的发育。
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 wildtype 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.