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Molecular Control of Cortical Neural Stem Cells

皮质神经干细胞的分子控制

基本信息

批准号：
7435392
负责人：
NENAD SESTAN
金额：
$ 31.96万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-01 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7435392
关键词：
Adhesions Apical Astrocytes Binding Sites Blocking Antibodies Brain Brain Diseases Cell Differentiation process Cell physiology Cells Cellular biology Cerebral cortex Co-Immunoprecipitations Complex Cultured Cells Dependence Development E-Cadherin Embryo Exhibits Facility Construction Funding Category Gene Expression Gene Silencing Genes Genetic Transcription Homeostasis In Vitro Invaded Lead Ligands Maintenance Mediating Membrane Molecular Mus Neuroglia Neurons Notch Signaling Pathway Numbers Placement Play Production Protein Binding Protein Overexpression Proteins RNA Interference Radial Regulation Research Personnel Role Signal Transduction Small Interfering RNA Specificity Staging Stem cells Surface System Techniques Testing Tissues Transcript Ventricular cell type gain of function in vivo insight jagged1 protein migration nerve stem cell neurogenesis neuronal guidance notch protein postnatal progenitor programs promoter relating to nervous system research study

项目摘要

DESCRIPTION (provided by applicant): Radial glial cells play a critical role in the construction of the mammalian cerebral cortex by first giving rise to neurons during early development, then providing guidance for neuronal migration, and at later stages, generating astrocytes. Abnormalities in radial glial development, differentiation, and guidance of neuronal migration lead to aberrant placement and connectivity of neurons. The decision of cortical radial glial cells to either multiply, differentiate or remain quiescent depends on an integration of multiple signaling mechanisms. The Notch signaling pathway is a key regulator of radial glial cell establishment and maintenance in the developing cerebral cortex. However, the molecular mechanisms underlying the specificity and context dependence of Notch signaling remain unclear. In this study, we will investigate the roles of a number of molecules in mediating Notch-dependent regulation of radial glial cell function. First, we will determine the specific and complementary roles of Delta-like 1 and Jagged 1 in regulating radial glial cell differentiation. Second, we will characterize putative interaction between Numb and Numb-like, and E-Cadherin in maintaining apicobasal polarity of radial glial cells. Finally, we will characterize the mechanism and function of oscillation in Notch activity during cortical neurogenesis. We will employ in vitro and in vivo systems and use both loss- and gain-of-function techniques to determine the functions and mechanisms of the above molecules. The elucidation of the molecular mechanisms of how Notch signaling and related molecules regulate cortical radial glial cell function as outlined in this proposal will advance the understanding of normal and abnormal brain development, and the stem cell biology.

描述(申请人提供)：放射状胶质细胞在哺乳动物大脑皮质的构建中起着关键作用，它首先在发育早期产生神经元，然后为神经元迁移提供指导，并在后期产生星形胶质细胞。放射状胶质细胞发育、分化和引导神经元迁移的异常导致神经元位置和连接的异常。皮质放射状胶质细胞是增殖、分化还是保持静止，取决于多种信号机制的整合。Notch信号通路是发育中的大脑皮层放射状胶质细胞建立和维持的关键调节因子。然而，Notch信号的特异性和上下文依赖性背后的分子机制仍然不清楚。在这项研究中，我们将研究一些分子在介导依赖Notch的放射状胶质细胞功能调节中的作用。首先，我们将确定Delta-like 1和Jagge1在调节放射状胶质细胞分化中的特异性和互补性作用。其次，我们将描述Numb和Numb样蛋白以及E-钙粘附素在维持放射状神经胶质细胞顶端基底极性方面可能存在的相互作用。最后，我们将描述在皮质神经发生过程中Notch活动振荡的机制和功能。我们将使用体外和体内系统，并使用功能丧失和功能获得技术来确定上述分子的功能和机制。阐明Notch信号及相关分子调节皮质放射状胶质细胞功能的分子机制将促进对正常和异常脑发育以及干细胞生物学的理解。