Stem Cells & Devel Cell：揭示调节神经干细胞分裂及分化的关键分子

pailishi

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作者：T.Shen 来源：生物谷 2012-8-2 23:59:129 h) l7 h6 N. w4 I  v5 T9 F: b

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来自新加坡A-STAR研究机构的研究者通过研究发现了某种分子组分可以有效阻止神经干细胞分裂，然而却可以促进其分化为不同类型的大脑细胞。
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近日，来自新加坡A-STAR研究机构的研究者通过研究发现了某种分子组分可以有效阻止神经干细胞分裂，然而却可以促进其分化为不同类型的大脑细胞。相关研究成果刊登在了近日的国际杂志Stem Cells和Developmental Cell上。' `$ \+ |6 l9 ?) s. E1 u: }( t

% T7 ^$ T! [5 ]; J& s在神经系统发育过程中，名为周期依赖性蛋白激酶（Cdks）的蛋白质可以紧密调节神经干细胞增殖和分化之间的平衡，但是在这个调节过程中扮演的角色却无人知道。
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( f/ l3 c5 W  v为了研究Cdks，研究者改造了缺乏编码Cdk2和Cdk4基因的突变体，Cdk2和Cdk4均可调节细胞分裂，研究者通过研究缺乏Cdk2和Cdk4的突变体动物模型发现其后脑部较大，而且相比正常动物，其脑室扩大了。而且这些突变体动物有较薄的新皮质，这就缺乏了正常细胞层的分界。进一步研究发现室管膜层包含着分裂的干细胞，这些包细胞未受到任何影响，但是其神经层已经缩小了46%。
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研究者随后用抗体染色方法对正常动物和突变体动物进行了相关实验，发现两组动物中的表达基因的细胞均需要自我更新，这也就说明Cdk2和Cdk4并没有改变干细胞的特性。尽管突变体的神经干细胞增值能力并未受到影响，但是其细胞更易于自发分化，深入研究揭示了增强的分化能力取决于细胞分裂的改变。
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( y3 O# J5 i, f) tCdk2和Cdk4的缺失可能会引发干细胞生化状态的改变，使其分化为神经元，同时研究者的研究结果也揭示了高水平的Cdk活性更倾向于神经干细胞的自我更新，而且降低其分化能力。（生物谷Bioon.com）/ ?2 e. Y- H% m# I3 h4 `9 Y: K

. \/ E& C4 c: }8 V4 T编译自：Two proteins that regulate cell division co-operate to control neuronal differentiation
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Developmental Cell杂志原文
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3 q/ K  W$ ^; M6 v- SLoss of Cdk2 and Cdk4 Induces a Switch from Proliferation to Differentiation in Neural Stem Cells†‡
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) v2 c, y2 h% LShuhui Lim1,§, Philipp Kaldis1,2,§,¶,*4 [, ~# i% x/ D5 f2 s
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During neurogenesis, cell cycle regulators play a pivotal role in ensuring proper proliferation, cell cycle exit, and differentiation of neural precursors. However, the precise role of cyclin-dependent kinases (Cdks) in these processes is not well understood. We generated Cdk2 and Cdk4 double knockout (DKO) mice and found a striking ablation of the intermediate zone and cortical plate in mouse embryonic brain. When neural stem cells (NSCs) were isolated and analyzed, DKO NSCs proliferated comparable to wild type as Cdk1 now binds to cyclin D1 and E1 and assumes the role vacated by the loss of Cdk2 and Cdk4 in phosphorylating Rb. Although compensation was sufficient for the maintenance of self-renewal and multilineage potential, DKO NSCs displayed an altered cell cycle profile and were more prone to neuronal differentiation. This was manifested in vivo as a marked reduction in S-phase length and an increased tendency for neurogenic divisions that prevented proper expansion of the basal progenitor pool. Our data thus demonstrate the induction of neurogenic divisions in the absence of critical mediators of G1/S transition—Cdk2 and Cdk4, and highlight their evolutionary importance in the determination of cortical thickness. Stem Cells2012;30:1509–1520

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