Regulation Of Cortical Neurogenesis By Apical Complex Proteins

顶端复合蛋白对皮质神经发生的调节

• 批准号: 8516826
• 负责人: Seonhee Kim
• 金额: $ 26.04万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8516826
• 关键词: Regulation; Cortical; Neurogenesis; Apical; Complex

DESCRIPTION (provided by applicant): Normal development of the cerebral cortex depends upon the successful control of proliferation and differentiation of cortical progenitor cells, which is tightly orchestrated by cellular and molecular events that balance the generation of early-born neurons with the maintenance of progenitors for later-born neurons. When this crucial developmental process does not occur properly, abnormalities in the cortical structure are a result, often leading to developmental disabilities such as mental retardation, epilepsy, and autism. Recent studies have shown that the function of apical complex proteins is important in maintaining the progenitor fate. Pals1 is a scaffolding protein and a central component of apical complex proteins in the neural progenitor cells. To delineate the molecular mechanisms that control progenitor proliferation by apical complex proteins, Pals1 conditional knockout mouse model was generated. Loss of Pals1 causes defects in self-renewal of neural epithelial progenitors, leading to their exit of the cell cycle prematurely. The cell fate changes seen in the Pals1-deficient mice are accompanied by aberrant distribution of apical complex proteins and adherens junction (AJ) proteins, and disrupted membrane structure. Based on these observations, we hypothesize that Pals1 orchestrates the control of neural progenitor proliferation and the ultimate fate of cells in the cerebral cortex by regulating membrane architecture and cell polarity through interaction with apical complex proteins and AJ components. To test this hypothesis, the function of Pals1 in cell fate decision of radial glia progenitors (RGPs), which generate the majority of neurons, will be examined. The direct function of Pals1 in the cell fate will be determined by characterizing the cell fate changes elicited by Pals1 loss in the RGPs, and by analyzing the changes in the polarized shape and distribution of proteins. To determine the Pals1 distribution and function in mitosis, we will examine the dynamics of Pals1 distribution during mitosis and follow the fate of daughter cells, depending on Pals1 inheritance or changes in subcellular localization of Pals1; and define the Pals1 function in progenitor division by analyzing the mitosis defects of Pals1-deficient RGPs through time-lapse imaging. Lastly, to delineate the molecular pathways that underlie Pals1 function of cell fate decision, we will examine the Pals1 function in regulating the formation of adhesive cell-cell junction by the assembly of the apical complex, and targeting of cadherins to AJ and the lateral cell junction. We will also explore the Pals1 function in establishment of local signaling(s) that is essential for cell fate decision by interaction with the Par complex. The results of this study will provide valuable information regarding how proliferation control of neural progenitor cells is regulated during normal development, and may lead to important insights about the mechanisms causing devastating neurodevelopmental disorders. PUBLIC HEALTH RELEVANCE: Abnormalities in the development of cerebral cortex often cause devastating neurological disorders such as mental retardation, autism and epilepsy. The studies of molecular mechanisms that control neural progenitor proliferation will provide not only the better understanding of normal development of cerebral cortex, but also knowledge about disease causing mechanism that may lead to the potential therapeutics and possible prevention in the future.

描述（由申请人提供）：大脑皮层的正常发育取决于皮层祖细胞增殖和分化的成功控制，这是由细胞和分子事件紧密协调的，这些事件平衡了早期出生神经元的产生和后期出生神经元祖细胞的维持。当这一关键的发育过程没有正常发生时，就会导致皮质结构异常，通常会导致发育障碍，如智力迟钝、癫痫和自闭症。近年来的研究表明，顶端复合体蛋白的功能在维持祖细胞命运中起着重要的作用。pal1是一种支架蛋白，是神经祖细胞顶端复合体蛋白的核心成分。为了阐明顶端复合体蛋白控制祖细胞增殖的分子机制，我们建立了Pals1条件敲除小鼠模型。Pals1缺失导致神经上皮祖细胞自我更新缺陷，导致其过早退出细胞周期。pals1缺陷小鼠的细胞命运变化伴随着顶端复合体蛋白和粘附连接（AJ）蛋白的异常分布，以及膜结构的破坏。基于这些观察结果，我们假设Pals1通过与顶端复合体蛋白和AJ成分相互作用，调节膜结构和细胞极性，从而协调控制神经祖细胞增殖和大脑皮层细胞的最终命运。为了验证这一假设，我们将研究Pals1在产生大多数神经元的径向胶质祖细胞（RGPs）的细胞命运决定中的功能。通过表征rgp中Pals1缺失引起的细胞命运变化，以及分析蛋白质极化形状和分布的变化，可以确定Pals1在细胞命运中的直接功能。为了确定Pals1在有丝分裂中的分布和功能，我们将研究Pals1在有丝分裂过程中的分布动态，并根据Pals1遗传或Pals1亚细胞定位的变化跟踪子细胞的命运；通过延时成像分析Pals1缺陷rgp的有丝分裂缺陷，明确Pals1在祖细胞分裂中的功能。最后，为了描述Pals1细胞命运决定功能的分子途径，我们将研究Pals1在通过顶端复合体的组装调节粘附细胞-细胞连接形成中的功能，以及钙粘蛋白靶向AJ和侧细胞连接。我们还将探讨通过与Par复合体的相互作用，Pals1在建立局部信号传导中的作用，这对细胞命运决定至关重要。本研究的结果将为神经祖细胞在正常发育过程中如何调节增殖控制提供有价值的信息，并可能对导致破坏性神经发育障碍的机制产生重要见解。