p27Kip1 and p57Kip2 regulate proliferation in distinct retinal progenitor cell populations
p27Kip1 and p57Kip2 regulate proliferation in distinct retinal progenitor cell populations
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DOI：
10.1523/jneurosci.21-12-04259.2001
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发表时间：
2001-06-15
影响因子：
5.3
通讯作者：
Cepko, CL
中科院分区：
文献类型：
--
作者：
Dyer, MA;Cepko, CL
在发育中的脊椎动物视网膜中，必须精确调节祖细胞增殖，以确保成熟组织的适当形成。细胞周期蛋白激酶抑制剂通过阻断细胞周期蛋白-细胞周期蛋白依赖性激酶复合物的活性而被认为是发育过程中增殖的重要调节剂。我们发现 p27(Kip1) 细胞周期蛋白激酶抑制剂在整个视网膜组织发生过程中调节祖细胞增殖。 p27(Kip1) 在视网膜祖细胞细胞周期的晚期 G(2)/早期 G(1) 期上调，在此期间它与主要的视网膜 D 型细胞周期蛋白 - 细胞周期蛋白 D1 相互作用。 p27（Kip1）缺陷的小鼠在整个发育过程中表现出有丝分裂细胞比例的增加以及广泛的细胞凋亡，特别是在视网膜组织发生的后期。有丝分裂视网膜祖细胞中逆转录病毒介导的 p27(Kip1) 过度表达导致细胞周期过早退出，但对 Muller 胶质细胞或双极细胞命运规范没有显着影响，如非洲爪蟾细胞周期蛋白激酶抑制剂 p27(Xic1) 所见。与 p27(Kip1) 的过度表达一致，缺乏 p27(Kip1) 的一个或两个等位基因的小鼠与野生型同窝小鼠保持每种主要视网膜细胞类型相同的相对比例。在胚胎发育阶段，当p27（Kip1）和p57（Kip2）在视网膜祖细胞中表达时，它们被发现存在于不同的群体中，直接证明不同的视网膜祖细胞在细胞周期调节因子的表达方面存在异质性。
In the developing vertebrate retina, progenitor cell proliferation must be precisely regulated to ensure appropriate formation of the mature tissue. Cyclin kinase inhibitors have been implicated as important regulators of proliferation during development by blocking the activity of cyclin-cyclin-dependent kinase complexes. We have found that the p27(Kip1) cyclin kinase inhibitor regulates progenitor cell proliferation throughout retinal histogenesis. p27(Kip1) is upregulated during the late G(2)/early G(1) phase of the cell cycle in retinal progenitor cells, where it interacts with the major retinal D-type cyclin-cyclin D1. Mice deficient for p27(Kip1) exhibited an increase in the proportion of mitotic cells throughout development as well as extensive apoptosis, particularly during the later stages of retinal histogenesis. Retroviral-mediated overexpression of p27(Kip1) in mitotic retinal progenitor cells led to premature cell cycle exit yet had no dramatic effects on Muller glial or bipolar cell fate specification as seen with the Xenopus cyclin kinase inhibitor, p27(Xic1). Consistent with the overexpression of p27(Kip1), mice lacking one or both alleles of p27(Kip1) maintained the same relative ratios of each major retinal cell type as their wild-type littermates. During the embryonic stages of development, when both p27(Kip1) and p57(Kip2) are expressed in retinal progenitor cells, they were found in distinct populations, demonstrating directly that different retinal progenitor cells are heterogeneous with respect to their expression of cell cycle regulators.