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: 9250221
• 负责人: Song-Hai Shi
• 金额: $ 45.51万
• 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/9250221
• 关键词: Address; Animals; Behavior; Binding Proteins; Brain; Cell Cycle; Cell division; Cell physiology; Cells; Centrosome; Cerebral cortex; Cognition; Continuous Positive Airway Pressure; Copying Processes; 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; Language; Light; Link; Methods; Microcephaly; Microtubules; Mission; Mitotic; Molecular Abnormality; Mothers; Movement; Mus; Neocortex; Neurodevelopmental Disorder; Neurons; Nuclear; Organelles; Perception; Phylogenetic Analysis; Plus End of the Microtubule; Population; Positioning Attribute; Production; Property; Proteins; Public Health; Publishing; Radial; Recruitment Activity; Regulation; Reporting; Research; Stem cells; Surface; Testing; United States National Institutes of Health; Ventricular; Writing; appendage; base; brain size; cilium biogenesis; daughter cell; disability; excitatory neuron; genetic approach; insight; 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）：大脑的指挥中心皮层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位于发育中的皮质的心室区（VZ）的放射状胶质祖细胞（RGPCs）的强大的不对称分裂来实现的。虽然在过去的二十年里，我们对发育中的皮层中RGPC分裂和神经发生的理解取得了很大的进展，但我们对皮层神经发生过程中中心体的精确调控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细胞器。该应用程序的目标是填补这一知识空白，这对于理解小头症的病因学和病理生理学也至关重要。小头症是一种神经发育障碍，其特征是由于发育中的皮层中神经元产生不足而导致大脑体积小。迄今为止，至少有8个常染色体隐性遗传原发性小头畸形（MCPH）位点和7个基因已被确定为常染色体隐性遗传原发性小头畸形（MCPH）。值得注意的是，所有已定义的MCPH基因都编码中心体蛋白，这强调了中心体在发育中的皮层正常神经元群体的产生中适当调节和功能的独特重要性。核心假设是，成熟中心体对于维持RGPCs在VZ（祖细胞生态位）中，并确保它们在发育中的皮层中正常分裂和存活至关重要。这一假设是在申请人实验室发表的强有力的初步数据的基础上制定的。在初步数据的指导下，这一假设将通过追求三个具体目标来验证：1)揭示间期和有丝分裂RGPCs中的中心体特性和行为；2)明确中心体在RGPCs中的功能；3)探索RGPCs中中心体行为的调控机制。本应用程序的实验重点是利用最先进的成像和小鼠遗传学方法，全面了解RGPCs中中心体在细胞周期中产生神经元并将其与小头畸形联系起来时的行为、功能和调控。在撰写本文时，很少有此类研究的报道。完成本课题的目标，不仅对RGPC分裂和皮层神经发生提供重要的认识，而且有助于明确由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。