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: 8550834
• 负责人: Seonhee Kim
• 金额: $ 31.65万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8550834
• 关键词: Adherens Junction; Adhesives; Alleles; Animal Model; Apical; Architecture; Autistic Disorder; Brain; Cadherins; Cell Cycle; Cell Polarity; Cell division; Cell physiology; Cells; Cerebral cortex; Complex; Decision Making; Defect; Development; Developmental Disabilities; Developmental Process; Disease; Dominant-Negative Mutation; Epilepsy; Epithelial; Equilibrium; Event; Future; Generations; Goals; Image; Intercellular Junctions; Invertebrates; Knock-out; Knockout Mice; Knowledge; Lateral; Lead; Length; Maintenance; Membrane; Membrane Potentials; Mental Retardation; Microcephaly; Mitosis; Mitotic; Mitotic spindle; Molecular; Monitor; Mus; Neurodevelopmental Disorder; Neuroepithelial; Neuroepithelial Cells; Neuroglia; Neurons; Pathway interactions; Phenotype; Play; Prevention; Proteins; Psyche structure; Radial; Regulation; Role; Scaffolding Protein; Shapes; Signal Transduction; Stem cells; Structure; Testing; Therapeutic; Time; base; cognitive function; daughter cell; insight; mouse model; nerve stem cell; nervous system disorder; neurogenesis; premature; progenitor; protein complex; protein distribution; public health relevance; recombinase; relating to nervous system; scaffold; self-renewal

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对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生成与祖细胞的维持对于后来出生的神经元。当这一关键的发育过程不能正常发生时，就会导致皮质结构异常，通常会导致智力低下、癫痫和自闭症等发育障碍。最近的研究表明，顶端复合蛋白的功能对于维持祖细胞命运非常重要。 Pals1 是一种支架蛋白，也是神经祖细胞中顶端复合体蛋白的核心成分。为了描述顶端复合蛋白控制祖细胞增殖的分子机制，建立了 Pals1 条件敲除小鼠模型。 Pals1 的缺失会导致神经上皮祖细胞的自我更新缺陷，导致它们过早退出细胞周期。 Pals1 缺陷小鼠中观察到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，我们假设 Pals1 通过与顶端复合蛋白和 AJ 成分相互作用来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。为了检验这一假设，我们将检查 Pals1 在产生大多数神经元的放射状胶质祖细胞 (RGP) 的细胞命运决定中的功能。 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极化形状和分布的变化来确定。为了确定 Pals1 在有丝分裂中的分布和功能，我们将检查有丝分裂期间 Pals1 分布的动态，并根据 Pals1 遗传或 Pals1 亚细胞定位的变化来跟踪子细胞的命运；并通过延时成像分析 Pals1 缺陷的 RGP 的有丝分裂缺陷，定义 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，我们将检查 Pals1 通过组装顶端复合物来调节粘附细胞-细胞连接形成的功能，以及钙粘蛋白靶向 AJ 和侧细胞的功能。交界处。我们还将探索 Pals1 在建立局部信号传导方面的功能，这对于通过与 Par 复合物相互作用来决定细胞命运至关重要。这项研究的结果将提供有关正常发育过程中如何调节神经祖细胞增殖控制的有价值的信息，并可能导致对导致破坏性神经发育障碍的机制的重要见解。 公共卫生相关性：大脑皮层发育异常通常会导致毁灭性的神经系统疾病，例如智力低下、自闭症和癫痫。对控制神经祖细胞增殖的分子机制的研究不仅可以更好地了解大脑皮层的正常发育，还可以提供有关疾病致病机制的知识，从而在未来提供潜在的治疗和可能的预防。

项目成果

Yap is required for ependymal integrity and is suppressed in LPA-induced hydrocephalus.

Yap 是室管膜完整性所必需的，并且在 LPA 诱导的脑积水中受到抑制。

• 发表时间: 2016-01-12
• 影响因子: 16.6
• 作者: Park, Raehee;Moon, Uk Yeol;Park, Jun Young;Hughes, Lucinda J;Johnson, Randy L;Cho, Seo;Kim, Seonhee
• 通讯作者: Kim, Seonhee

Impaired Reelin-Dab1 Signaling Contributes to Neuronal Migration Deficits of Tuberous Sclerosis Complex.

Reelin-Dab1 信号传导受损会导致结节性硬化症的神经元迁移缺陷。

• DOI: 10.1016/j.celrep.2015.07.013
• 发表时间: 2015-08-11
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Moon UY;Park JY;Park R;Cho JY;Hughes LJ;McKenna J 3rd;Goetzl L;Cho SH;Crino PB;Gambello MJ;Kim S
• 通讯作者: Kim S