Filamin a regulates neural progenitor proliferation and cortical size through Wee1-dependent Cdk1 phosphorylation.
Filamin a regulates neural progenitor proliferation and cortical size through Wee1-dependent Cdk1 phosphorylation.
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DOI：
10.1523/jneurosci.0894-12.2012
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发表时间：
2012-05-30
期刊：
影响因子：
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通讯作者：
Sheen VL
中科院分区：
文献类型：
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作者：
Lian G;Lu J;Hu J;Zhang J;Cross SH;Ferland RJ;Sheen VL
细胞凋亡相关蛋白不仅在调节细胞形态和迁移中起关键作用，而且在增殖中也起关键作用。细胞因子相关基因细丝蛋白A（FlnA）的突变导致人类室周异位症（PH）。PH是一种神经干细胞发育障碍，其特征在于沿着心室上皮的祖细胞沿着破坏，随后形成异位神经元结节。细胞骨架动力学的FlnA依赖性调节被认为指导神经祖细胞迁移和增殖。在这里，我们表明，胚胎FlnA基因敲除小鼠表现出大脑大小的减少，随着时间的推移，神经祖细胞数量下降。祖细胞数量的下降不是由于细胞死亡或过早分化的变化，而是由于细胞周期持续时间延长。FlnA的抑制导致整个细胞周期长度的延长，主要是在M期。FlnA的丢失损害了细胞周期蛋白b1相关蛋白的降解，从而延迟了有丝分裂的发生和进展。我们发现，cdk1激酶Wee1结合FlnA，表现出增加的表达水平后，FlnA功能的损失，并与cdk1的磷酸化增加。磷酸化的cdk1抑制后期促进复杂降解系统的激活，这是负责细胞周期蛋白b1降解和有丝分裂的进展。总的来说，我们的研究结果证明了一种分子机制，即FlnA损失损害G2至M期进入，导致细胞周期延长，损害神经祖细胞增殖，并减少脑体积。
Cytoskeleton-associated proteins play key roles not only in regulating cell morphology and migration but also in proliferation. Mutations in the cytoskeleton-associated gene filamin A (FlnA) cause the human disorder periventricular heterotopia (PH). PH is a disorder of neural stem cell development that is characterized by disruption of progenitors along the ventricular epithelium and subsequent formation of ectopic neuronal nodules. FlnA-dependent regulation of cytoskeletal dynamics is thought to direct neural progenitor migration and proliferation. Here we show that embryonic FlnA null mice exhibited a reduction in brain size, and decline in neural progenitor numbers over time. The drop in the progenitor population was not attributable to cell death or changes in premature differentiation, but to prolonged cell cycle duration. Suppression of FlnA led to prolongation of the entire cell cycle length, principally in M-phase. FlnA loss impaired degradation of cyclin b1-related proteins, thereby delaying the onset and progression through mitosis. We found that the cdk1 kinase Wee1 bound FlnA, demonstrated increased expression levels after loss of FlnA function, and was associated with increased phosphorylation of cdk1. Phosphorylation of cdk1 inhibited activation of the anaphase promoting complex degradation system, which was responsible for cyclin b1 degradation and progression through mitosis. Collectively, our results demonstrate a molecular mechanism whereby FlnA loss impaired G2 to M phase entry, leading to cell cycle prolongation, compromised neural progenitor proliferation, and reduced brain size.