Centrosome Regulation and Function Associated with Microcephaly

与小头畸形相关的中心体调节和功能

• 批准号: 8759931
• 负责人: Song-Hai Shi
• 金额: $ 44.86万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8759931
• 关键词: Address; Animals; Behavior; Binding Proteins; Brain; Cell Cycle; Cell division; Cell physiology; Cells; Centrosome; Cerebral cortex; Cognition; Continuous Positive Airway Pressure; Data; Daughter; Development; Drug abuse; Early Diagnosis; Early treatment; Ensure; Etiology; Exhibits; Exposure to; Foundations; Functional disorder; Future; Genes; Genetic; Goals; Human; Image; Inherited; Interphase; Intrinsic factor; Knowledge; Label; Laboratories; Light; Link; Methods; Microcephaly; Microtubules; Mission; Mitotic; Molecular Abnormality; Mothers; Movement; Mus; Neocortex; Neurons; Nuclear; Organelles; Plus End of the Microtubule; Population; Positioning Attribute; Process; Production; Property; Proteins; Public Health; Publishing; Radial; Regulation; Reporting; Research; Stem cells; Surface; Testing; Ventricular; Writing; appendage; base; brain size; cilium biogenesis; daughter cell; developmental disease; disability; excitatory neuron; insight; language perception; neocortical; nerve stem cell; neurogenesis; prenatal exposure; prevent; public health relevance

DESCRIPTION (provided by applicant): Proper development of the cortex, the command center of the brain, entails extensive production of neurons. This is largely achieved through the robust asymmetric division of radial glial progenitor cells (RGPCs) residing in the ventricular zone (VZ) of the developing cortex. While excellent progress has been made over the past twenty years in our understanding of RGPC division and neurogenesis in the developing cortex, our knowledge of the precise regulation and function of the centrosome, a key subcellular organelle for microtubule organization, cell division and ciliogenesis, during cortical neurogenesis remains limited. The goal of this application is to fill this knowledge gap, which wil also be crucial for understanding the etiology and pathophysiology of microcephaly, a neuro-developmental disorder that is characterized by small brain size as a result of deficient neuron production in the developing cortex. To date, at least eight autosomal recessive primary microcephaly (MCPH) loci and seven genes have been identified for autosomal recessive primary microcephaly (MCPH). Remarkably, all the defined MCPH genes encode centrosomal proteins, underscoring the unique importance of proper centrosome regulation and function in the production of normal neuron populations in the developing cortex. The central hypothesis is that the mature centrosome is essential for maintaining RGPCs in the VZ - a progenitor cell niche - and ensuring their proper division and survival in the developing cortex. This hypothesis has been formulated on the basis of the strong published and preliminary data produced in the applicant's laboratory. Guided by preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Reveal centrosome properties and behavior in interphase and mitotic RGPCs; 2) Define the functions of the centrosome in RGPCs; and, 3) Explore the mechanisms that regulate centrosome behavior in RGPCs. The experimental focus of this application is to provide a comprehensive understanding of the behavior, function and regulation of the centrosome in RGPCs as they proceed through the cell cycle to produce neurons and link it to microcephaly, using state-of-the- art imaging and mouse genetic approaches. As of this writing, few such studies have been reported. Accomplishing the aims in this project will not only provide important insights into RGPC division and cortical neurogenesis, but also help to define the cellular basis of microcephaly caused by genetic abnormalities, and thereby provide new ideas for early diagnosis and treatment.

描述（由申请人提供）：大脑皮层（大脑的指挥中心）的正常发育需要大量神经元的产生。这在很大程度上是通过放射状胶质祖细胞（RGPC）的强大的不对称分裂居住在发育皮层的脑室区（VZ）。虽然在过去的二十年里，我们在了解发育中的皮层中的RGPC分裂和神经发生方面取得了很大的进展，但我们对中心体的精确调节和功能的了解仍然有限，中心体是微管组织，细胞分裂和纤毛发生的关键亚细胞器。本申请的目标是填补这一知识空白，这对于理解小头畸形的病因学和病理生理学也至关重要，小头畸形是一种神经发育障碍，其特征在于由于发育中的皮层中神经元产生不足而导致的脑体积小。迄今为止，至少有8个常染色体隐性原发性小头畸形（MCPH）基因座和7个基因已被确定为常染色体隐性原发性小头畸形（MCPH）。值得注意的是，所有定义的MCPH基因编码的中心体蛋白，强调了独特的重要性，适当的中心体的调节和功能，在正常的神经元群体的生产在发育中的皮层。核心假设是成熟的中心体对于维持VZ中的RGPCs-祖细胞龛-并确保其在发育中的皮质中正确分裂和存活是必不可少的。这一假设是根据申请人实验室所产生的强有力的已发表和初步数据制定的。在初步数据的指导下，将通过追求三个具体目标来检验这一假设：1）揭示间期和有丝分裂期RGPC中中心体的特性和行为; 2）定义RGPC中中心体的功能;和，3）探索调节RGPC中中心体行为的机制。本申请的实验重点是使用最先进的成像和小鼠遗传方法，全面了解RGPC中中心体的行为，功能和调节，因为它们通过细胞周期产生神经元并将其与小头畸形联系起来。在撰写本文时，很少有这样的研究报告。本项目的实现不仅将为RGPC分裂和皮层神经发生提供重要的见解，而且有助于确定遗传异常引起的小头畸形的细胞基础，从而为早期诊断和治疗提供新的思路。