Roles of cell cycle regulatory protein p27 in murine neocortical histogenesis

细胞周期调节蛋白p27在小鼠新皮质组织发生中的作用

基本信息

批准号：
13670837
负责人：
TAKAHASHI Takao
金额：
$ 2.18万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670837/
关键词：
cerebral histogenesis cell cycle development mouse neuronal progenitor CDK 神経系前駆細胞

项目摘要

p27^<kip1> is a cell cycle regulatory protein that inhibits G1 phase progression and induces cell differentiation. In p27^<kip1> knockout mouse (p27KO), the size of the brain is increased by about 30 %. We previously observed that both thickness and number of non-GABAergic neurons in the cortical layers II-IV were significantly increased in p27KO as compared to the WT littermates. These suggest that output from the NPCs in the middle to late period of neuronogenesis was increased by loss of function of p27^<kip1>. To investigate the histogenetic mechanisms of the cortical malformation in p27KO, we have studied proliferation and differentiation characteristics of the NPCs in the p27KO at embryonic day 14 (E14).The cell cycle length of the NPCs at E14 was indistinguishable between p27KO and WT. However, the number of the newly differentiated neurons (Q cells) at E14 was reduced in p27KO. The consequence is that there is proliferative augmentation of NPCs in the p27KO animals at E14. The distribution pattern of the Q cells in the p27KO was also abnormal. The exit behavior of Q cells from the proliferative epithelium is bimodal in both genotypes ; partitioned into rapidly and slowly exiting subpopulations. The reduction in the Q fraction in the p27KO is assignable entirely to the rapidly exiting subset of Q cells.The neocortical malformation in the p27KO is likely to be attributable to an abnormal pattern of the ascent of Q fraction during the middle phase of neuronogenetic interval.

p27^<kip1> 是一种细胞周期调节蛋白，可抑制 G1 期进展并诱导细胞分化。在 p27^<kip1> 敲除小鼠 (p27KO) 中，大脑大小增加了约 30%。我们之前观察到，与 WT 同窝小鼠相比，p27KO 中皮质层 II-IV 中非 GABA 能神经元的厚度和数量均显着增加。这些表明，在神经元发生的中后期，NPC 的输出因 p27^<kip1> 功能的丧失而增加。为了研究p27KO皮质畸形的组织遗传学机制，我们研究了胚胎第14天（E14）时p27KO中NPC的增殖和分化特征。E14时NPC的细胞周期长度在p27KO和WT之间无法区分。然而，p27KO 中 E14 新分化神经元（Q 细胞）的数量减少。结果是 p27KO 动物中的 NPC 在 E14 时出现增殖性增加。 p27KO中Q细胞的分布模式也异常。 Q 细胞从增殖上皮细胞的退出行为在两种基因型中都是双峰的。分为快速退出亚群和缓慢退出亚群。 p27KO 中 Q 分数的减少完全归因于 Q 细胞亚群的快速退出。p27KO 中的新皮质畸形可能归因于神经发生间隔中期 Q 分数上升的异常模式。