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

• 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

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，脑的大小增加了约30%。我们之前观察到，与WT幼崽相比，p27KO的皮质层II-IV的非gaba能神经元的厚度和数量都显著增加。这些结果表明，NPCs在神经发生中后期的输出量因p27^<kip1>的功能丧失而增加。为了研究p27KO皮质畸形的组织发生机制，我们研究了胚胎14天（E14） p27KO中NPCs的增殖和分化特征。p27KO和WT在E14时NPCs的细胞周期长度没有区别，但p27KO在E14时新分化的神经元（Q细胞）数量减少。结果是在E14的p27KO动物中npc的增殖增强。p27KO中Q细胞的分布模式也异常。在两种基因型中，Q细胞从增殖上皮中退出的行为是双峰的；分成快速和缓慢退出的亚种群。p27KO中Q分数的降低完全归因于快速退出的Q细胞子集。p27KO的新皮质畸形可能是由于神经发生间隔中期Q分数上升的异常模式所致。

项目成果

Cai L, Hayes NL, Takahashi T, Caviness VS Jr, Nowakowski RS.: "Size distribution of retrovirally marked lineages matches prediction from population measurements of cell cycle behavior"J Neurosci Res. 69-6. 731-744 (2002)

Cai L、Hayes NL、Takahashi T、Caviness VS Jr、Nowakowski RS.：“逆转录病毒标记谱系的大小分布与细胞周期行为群体测量的预测相匹配”J Neurosci Res。

Takahashi T: "Handbook of Developmental Cognitive Neuroscience"Eds. Nelson CA, Luciana M. The MIT Press, Cambridge.. 3-22 (2001)

高桥 T：《发育认知神经科学手册》Eds。

Mitsuhashi T: "Overexpression of p27Kip1 lengthens G1-phase in a mouse model that targets inducible gene expression to CNS progenitor cells"Proc Natl Acad Sci USA. 98. 6435-6440 (2001)

Mitsuhashi T：“p27Kip1 的过度表达延长了小鼠模型中的 G1 期，该模型将诱导基因表达靶向 CNS 祖细胞”Proc Natl Acad Sci USA。

Cai L: "Size distribution of retrovirally marked lineages matches prediction from population measurements of cell cycle behavior"J Neurosci Res. 69. 731-744 (2002)

蔡 L：“逆转录病毒标记谱系的大小分布与细胞周期行为群体测量的预测相匹配”J Neurosci Res。

Takahashi T, Caviness VS Jr, Bhide PG.: "Analysis of cell generation in the telencephalic neuroepithelium"Methods Mol Biol. 101-113 (2002)

Takahashi T、Caviness VS Jr、Bhide PG.：“端脑神经上皮中细胞生成的分析”方法 Mol Biol。