The Lis1-Nde1 pathway in cerebral cortical development

大脑皮层发育中的 Lis1-Nde1 通路

• 批准号: 8301707
• 负责人: Yuanyi Feng
• 金额: $ 27.07万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-20 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8301707
• 关键词: Actins; Adhesions; Affect; Binding; Binding Proteins; Biological; Brain; Cell Adhesion; Cell Adhesion Molecules; Cell Cycle; Cell membrane; Cell physiology; Cell surface; Cell-Cell Adhesion; Cells; Cellular biology; Cerebral cortex; Cerebrum; Clinical; Complex; Correlation Studies; Cortical Malformation; Coupled; Cytoplasmic Protein; Cytoskeleton; Defect; Destinations; Development; Disease; Dynein ATPase; Dystroglycan; Elements; Epilepsy; Equilibrium; Extracellular Matrix; Gene Mutation; Genes; Genetic; Glycoproteins; Health; Hereditary Disease; Intractable Epilepsy; Lateral; Lead; Link; Mediating; Membrane Part; Mental Retardation; Microtubules; Mitotic; Mitotic spindle; Molecular; Morphogenesis; Morphology; Mus; Mutant Strains Mice; Mutation; Neural tube; Neuroepithelial; Neuronal Differentiation; Neurons; Other Genetics; Pathogenesis; Pathway interactions; Pattern; Phenotype; Production; Profound Mental Retardation; Proteins; Radial; Regulation; Role; Series; Shapes; Structure; Syndrome; Testing; Work; design; developmental disease; developmental genetics; dosage; functional loss; in vivo; infant death; insight; lissencephaly; malformation; migration; mutant; nerve stem cell; neurogenesis; neurogenetics; neuronal survival; progenitor; protein protein interaction; relating to nervous system; research study; self-renewal; tool

DESCRIPTION (provided by applicant): Developmental genetic malformations of the cerebral cortex underlie a large fraction of clinical cases of epilepsy and mental retardation. A powerful tool for understanding these developmental disorders is to analyze their causative genes. Heterozygous mutations of the LIS1 gene are known to cause lissencephaly (smooth brain), a severe neurogenetic syndrome manifested by intractable epilepsy, profound mental retardation and early infantile death. LIS1 gene encodes a cytoplasmic protein with no apparent intrinsic enzymatic activity; its molecular and cellular function may act via protein-protein interactions. We show that LIS1 interacts with Nde1 both physically and functionally. By analyzing an allelic series of Lis1-Nde1 double mutant mice, we demonstrated that Lis1 and Nde1 form a dosage dependent complex in regulating the self-renewal and differentiation of neural progenitors. Lis1-Nde1 double loss of functional mutations resulted in severe mitotic, morphological and adhesion defects of neural progenitors at the onset of cerebral cortical neurogenesis, leading to an over 80% reduction in the size of the cerebral cortex and severe disorganizations of cortical neurons. We propose to perform detailed analyses on cortical developmental defects of Lis1 and Nde1 mutant mice in Specific Aim 1 to understand how the proliferative self-renewal and the neurogenic differentiation of neural progenitors are controlled by their basic structural features such as morphology, mitotic pattern, lateral adhesions and cytoarchitectural organizations. We will also explore the cell molecular mechanisms that underlie the neurogenesis control by the Lis1-Nde1 complex in Specific Aim 2 through studying Lis1- Nde1 mutant progenitors in cultures and analyzing Nde1 binding proteins. The proposed work will help to understand the molecular control of cortical neurogenesis by the Lis1- Nde1 pathway, and will also gain a broader insight into mechanisms governing cerebral cortex development as well as pathogenesis of lissencephaly and other genetic cortical malformation diseases. PUBLIC HEALTH RELEVANCE: Mutations of the LIS1 gene cause lissencephaly syndrome (smooth brain), a severe developmental genetic disorder with a malformed cerebral cortex, intractable epilepsy and profound mental retardation. The proposal outlines combined mouse genetic and cell biological experiments to study the function of LIS1 and its associated Nde1 genes in regulating the self- renewal and neurogenesis during cerebral cortical development.

描述（由申请人提供）： 大脑皮层的发育性遗传畸形是癫痫和精神发育迟滞临床病例的很大一部分。了解这些发育障碍的一个有力工具是分析其致病基因。 LIS1 基因的杂合突变已知会导致无脑畸形（光滑脑），这是一种严重的神经遗传综合征，表现为顽固性癫痫、严重智力低下和婴儿早期死亡。 LIS1 基因编码一种细胞质蛋白，没有明显的内在酶活性；其分子和细胞功能可能通过蛋白质-蛋白质相互作用发挥作用。我们证明 LIS1 与 Nde1 在物理和功能上都有相互作用。通过分析Lis1-Nde1双突变小鼠的等位基因系列，我们证明Lis1和Nde1形成剂量依赖性复合物来调节神经祖细胞的自我更新和分化。 Lis1-Nde1双重功能缺失突变导致大脑皮层神经发生开始时神经祖细胞出现严重的有丝分裂、形态和粘附缺陷，导致大脑皮层尺寸缩小80%以上，皮层神经元严重紊乱。我们建议对Specific Aim 1中Lis1和Nde1突变小鼠的皮质发育缺陷进行详细分析，以了解神经祖细胞的增殖自我更新和神经源性分化是如何受其基本结构特征（如形态、有丝分裂模式、横向粘附和细胞结构组织）控制的。我们还将通过研究培养物中的 Lis1-Nde1 突变祖细胞并分析 Nde1 结合蛋白，探索特定目标 2 中 Lis1-Nde1 复合物控制神经发生的细胞分子机制。拟议的工作将有助于了解 Lis1-Nde1 通路对皮质神经发生的分子控制，还将更广泛地了解控制大脑皮层发育的机制以及无脑畸形和其他遗传性皮质畸形疾病的发病机制。 公共健康相关性：LIS1 基因突变会导致无脑畸形综合征（光滑脑），这是一种严重的发育性遗传性疾病，伴有大脑皮层畸形、顽固性癫痫和严重智力低下。该提案概述了结合小鼠遗传和细胞生物学实验来研究 LIS1 及其相关 Nde1 基因在调节大脑皮层发育过程中自我更新和神经发生中的功能。