Bone Morphogenetic Protein-6 Promotes Cerebellar Granule Neurons Survival by Activation of the MEK/ERK/CREB Pathway
Bone Morphogenetic Protein-6 Promotes Cerebellar Granule Neurons Survival by Activation of the MEK/ERK/CREB Pathway
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DOI：
10.1091/mbc.e09-05-0424
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发表时间：
2009-12-15
影响因子：
3.3
通讯作者：
Rodriguez-Alvarez, Jose
中科院分区：
文献类型：
--
作者：
Barneda-Zahonero, Bruna;Minano-Molina, Alfredo;Rodriguez-Alvarez, Jose
骨形态发生蛋白（BMPs）参与小脑颗粒细胞（CGC）的生成和生后分化。在这里，我们研究了BMP对这些神经元存活的最终作用。缺乏去极化导致CGC在体内通过细胞凋亡死亡，这是一种在体外通过剥夺培养的CGC中的高钾来模拟的现象。我们已经发现，BMP-6，而不是BMP-7，能够阻断低钾介导的CGCs凋亡。BMP-6的神经保护作用并不伴随着Smad易位到细胞核的增加，这表明不涉及经典途径。相比之下，BMP-6激活MEK/ERK/CREB通路是其神经保护作用所必需的，这涉及抑制半胱天冬酶活性和增加Bcl-2蛋白水平。参与CGC存活调节的其他途径，如c-Jun末端激酶和磷脂酰肌醇3-激酶（PI 3 K）-Akt/PKB，不受BMP-6的影响。此外，BMP-7不能激活MEK/ERK/CREB通路可以解释其不能保护CGCs免于低钾介导的凋亡。因此，这项研究表明，BMP-6通过非经典的MEK/ERK/CREB途径发挥作用，对CGC的生存起着至关重要的作用。
Bone morphogenetic proteins (BMPs) have been implicated in the generation and postnatal differentiation of cerebellar granule cells (CGCs). Here, we examined the eventual role of BMPs on the survival of these neurons. Lack of depolarization causes CGC death by apoptosis in vivo, a phenomenon that is mimicked in vitro by deprivation of high potassium in cultured CGCs. We have found that BMP-6, but not BMP-7, is able to block low potassium-mediated apoptosis in CGCs. The neuroprotective effect of BMP-6 is not accompanied by an increase of Smad translocation to the nucleus, suggesting that the canonical pathway is not involved. By contrast, activation of the MEK/ERK/CREB pathway by BMP-6 is necessary for its neuroprotective effect, which involves inhibition of caspase activity and an increase in Bcl-2 protein levels. Other pathways involved in the regulation of CGC survival, such as the c-Jun terminal kinase and the phosphatidylinositol 3-kinase (PI3K)-Akt/PKB, were not affected by BMP-6. Moreover, failure of BMP-7 to activate the MEK/ERK/CREB pathway could explain its inability to protect CGCs from low potassium-mediated apoptosis. Thus, this study demonstrates that BMP-6 acting through the noncanonical MEK/ERK/CREB pathway plays a crucial role on CGC survival.