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）：脑皮质的正常发育取决于成功控制皮质祖细胞的增殖和分化，这是由细胞和分子事件紧密地策划的，这些事件平衡了早期出生的神经元的产生，并维持后代神经元的祖细胞。当这种关键的发育过程无法正确发生时，皮质结构的异常是结果，通常会导致发育障碍，例如智力迟缓，癫痫和自闭症。最近的研究表明，顶端复合物蛋白的功能对于维持祖细胞命运很重要。 PALS1是一种脚手架蛋白，也是神经祖细胞中根尖复合物蛋白的中心成分。为了描述通过顶端复合蛋白控制祖细胞增殖的分子机制，生成了PALS1条件基因敲除小鼠模型。 PALS1的丧失导致神经上皮祖细胞的自我更新中的缺陷，导致其过早地退出细胞周期。在PALS1缺陷型小鼠中看到的细胞命运变化伴随着顶端复合物蛋白和粘附连接（AJ）蛋白的异常分布，以及膜结构破坏。基于这些观察结果，我们假设PALS1通过调节膜结构和细胞极性通过与顶端复杂蛋白和AJ成分的相互作用来调节膜结构和细胞极性，从而策划了对神经祖细胞增殖的控制和细胞中细胞的最终命运。为了检验这一假设，将检查PALS1在产生大多数神经元的径向胶质祖细胞（RGP）的细胞命运决策中的功能。 PALS1在细胞命运中的直接功能将通过表征RGP中PALS1丢失引起的细胞命运变化以及分析蛋白质的偏振形状和分布的变化来确定。为了确定有丝分裂中的PALS1分布和功能，我们将检查有丝分裂过程中PALS1分布的动力学，并遵循子细胞的命运，这取决于PALS1遗传或PALS1的亚细胞定位的变化；并通过分析通过延时成像分析PALS1缺陷型RGP的有丝分裂缺陷来定义PALS1功能。最后，为了描绘细胞命运决定的PALS1功能的分子途径，我们将检查PALS1通过顶端复合物的组装来调节粘合剂细胞 - 细胞连接形成的功能，并靶向钙粘着蛋白对AJ和AJ和外侧细胞连接。我们还将探索PALS1在建立局部信号传导中的函数，这对于通过与PAR复合物相互作用而对细胞命运决策至关重要。这项研究的结果将提供有关在正常发育过程中如何调节神经祖细胞的增殖控制的有价值信息，并可能导致有关导致毁灭性神经发育障碍的机制的重要见解。 公共卫生相关性：脑皮质发展的异常，通常会导致诸如智力低下，自闭症和癫痫病等毁灭性神经系统疾病。控制神经祖细胞增殖的分子机制的研究不仅会更好地理解大脑皮质的正常发育，而且还提供了有关疾病的知识，从而导致可能导致潜在的疗法和未来的预防。