Proliferation of hippocampal progenitors relies on p27-dependent regulation of Cdk6 kinase activity
Proliferation of hippocampal progenitors relies on p27-dependent regulation of Cdk6 kinase activity
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DOI：
10.1007/s00018-018-2832-x
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发表时间：
2018-10-01
影响因子：
8
通讯作者：
Malgrange, Brigitte
中科院分区：
文献类型：
--
作者：
Caron, Nicolas;Genin, Emmanuelle C.;Malgrange, Brigitte
神经干细胞在海马体中终生产生颗粒齿状神经元。一旦激活，这些干细胞产生快速增殖的祖细胞，在分化成神经元之前完成几轮分裂。尽管人们已经深入研究了调节干细胞激活的机制，但迄今为止，人们很少关注允许祖细胞库扩大的内在机制。细胞周期蛋白Cdk 6正调控海马祖细胞的增殖，但涉及的机制仍然难以捉摸。虽然Cdk 6主要作为细胞周期激酶发挥作用，但它也可以作为癌细胞和造血干细胞中的转录调节因子。使用小鼠遗传学，我们在这里表明，Cdk 6在海马神经发生的功能，特别是依赖于其激酶活性。本研究还揭示了海马前体细胞中Cdk 6的特异性调控机制。与细胞周期的经典模型相反，我们观察到Cip/Kip家族成员p27，而不是Ink 4家族，负调控成年海马中的Cdk 6。总之，我们的数据揭示了一个独特的，细胞类型特异性的调节机制控制海马祖细胞的扩增，其中Cdk 6激酶活性由p27调节。
Neural stem cells give rise to granule dentate neurons throughout life in the hippocampus. Upon activation, these stem cells generate fast proliferating progenitors that complete several rounds of divisions before differentiating into neurons. Although the mechanisms regulating the activation of stem cells have been intensively studied, little attention has been given so far to the intrinsic machinery allowing the expansion of the progenitor pool. The cell cycle protein Cdk6 positively regulates the proliferation of hippocampal progenitors, but the mechanism involved remains elusive. Whereas Cdk6 functions primarily as a cell cycle kinase, it can also act as transcriptional regulator in cancer cells and hematopoietic stem cells. Using mouse genetics, we show here that the function of Cdk6 in hippocampal neurogenesis relies specifically on its kinase activity. The present study also reveals a specific regulatory mechanism for Cdk6 in hippocampal progenitors. In contrast to the classical model of the cell cycle, we observe that the Cip/Kip family member p27, rather than the Ink4 family, negatively regulates Cdk6 in the adult hippocampus. Altogether, our data uncover a unique, cell type-specific regulatory mechanism controlling the expansion of hippocampal progenitors, where Cdk6 kinase activity is modulated by p27.