Molecular and cellular mechanism of Microcephaly

小头畸形的分子和细胞机制

• 批准号: 8133438
• 负责人: ARNOLD KRIEGSTEIN
• 金额: $ 32.42万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8133438
• 关键词: Adoption; Attention deficit hyperactivity disorder; Autistic Disorder; Axon; Behavior; Biological Assay; Birth; Brain; Cell Cycle; Cell Cycle Regulation; Cell Line; Cell division; Cells; Centrosome; Cerebral cortex; Cerebrum; Complex; Continuous Positive Airway Pressure; Cortical Dysplasia; DNA Repair; Data; Daughter; Defect; Development; Disease; Drosophila genus; Drug Compounding; Embryo; Epilepsy; Etiology; Exhibits; Fluorescence; Focal Seizure; Generalized seizures; Genes; Genetic Techniques; Goals; Head circumference; Human; Image; Immature Centriole; Immigration; In Vitro; Inborn Genetic Diseases; Individual; Inherited; Knowledge; LIS1 protein; Label; Laser Scanning Microscopy; Light; Link; Mature Centriole; Mental Retardation; Mental disorders; Methods; Microcephaly; Microgyria; Microtubule-Associated Proteins; Microtubules; Mild mental retardation; Mitosis; Molecular; Molecular Genetics; Monitor; Mothers; Mus; Mutate; Mutation; Neocortex; Neurodevelopmental Disorder; Neuroglia; Neurologic; Neurons; Nuclear; Nuclear Translocation; Pathogenesis; Patients; Phase; Play; Population; Positioning Attribute; Process; Proteins; RNA Interference; Radial; Research; Resolution; Rodent; Rodent Model; Role; Schizophrenia; Series; Shapes; Slice; Somatic Cell; Stem cells; Structure; Techniques; Testing; Time; base; brain size; brain volume; cell determination; daughter cell; in vivo; induced pluripotent stem cell; innovation; insight; loss of function; migration; neocortical; nerve stem cell; nervous system disorder; neuroblast; neurogenesis; neuropsychiatry; progenitor; public health relevance; self-renewal; stem; time use; transcription factor; two-photon

DESCRIPTION (provided by applicant): Autosomal recessive primary microcephaly (MCPH) is a genetically and clinically heterogeneous disease defined by a decrease in head circumference at birth. Patients often have a broad spectrum of neurological problems, including mental retardation, focal or generalized seizures, hyperactivity, and attention deficit disorder. The decrease in brain volume without major architectonic abnormalities most likely stems from a primary defect in neurogenesis and or neuronal migration. Five of eight MCPH genes localize to the centrosome during all or part of the cell cycle. In vitro studies provide evidence that these genes play roles in essential centrosomal functions such as cell cycle regulation. Nonetheless, the mechanism of MCPH in brain development is still poorly understood. The long-term goal of this project is to profile the role of MCPH genes in neocortical development and disease pathogenesis. The objectives are to uncover the molecular and cellular controls of MCPH genes on neurogenesis and to define how centrosomal proteins regulate the mode of division (symmetric or asymmetric), neuronal migration and differentiation. Recent studies from our lab and others have demonstrated that radial glial cells are a major population of neuronal progenitor cells. They divide asymmetrically to self-renew and give rise to cortical neurons. Asymmetric centrosome inheritance is believed to regulate the differential behavior of self-renewing progenitors versus differentiating progeny in the embryonic mouse neocortex. Centrosome defects in Drosophila do not dramatically perturb mitosis in most somatic cells, but the asymmetric division of larval neuroblasts is noticeably disrupted, underscoring the particular significance of centrosome behavior for asymmetric cell division of progenitor cells and determination of daughter cell fate. Furthermore, the centrosome is the primary anchor for microtubules, enabling the differentiating neuron to initiate and extend an axon, a key process of neuron differentiation. Based on these observations, the central hypothesis of this application is that the MCPH genes control neurogenesis, neuronal migration, and differentiation in the developing cortex. Guided by strong preliminary data this hypothesis will be tested by pursuing four specific aims: 1) To determine the molecular and cellular mechanism by which MCPH genes regulate radial glial cell division; 2) To explore the function of MCPH genes in regulating asymmetric inheritance of mother versus daughter centrosomes and daughter cell fate; 3) To define the function of MCPH genes in regulating neuronal migration and differentiation in the developing cortex; and 4) To validate the relevance of findings in the mouse to the pathogenesis of human MCPH using patient induced pluripotent stem (iPS) cells. With innovative approaches including high-temporal time-lapse imaging and molecular genetic techniques, the proposed research will provide new insights into the pathogenesis of MCPH and expand our knowledge of brain development. Moreover, the results of this study may shed light on mechanisms relevant to the etiology of many neurological and psychiatric disorders related to cortical function. PUBLIC HEALTH RELEVANCE: This study investigates the molecular and cellular mechanisms of human microcephaly, an important and under-investigated neurodevelopmental disorder. Understanding how microcephaly develops is important not only for a deeper understanding brain development, but also to advance our understanding and potential treatment of a variety of other neurodevelopmental disorders caused through defects in cerebral cortex development including mental retardation, epilepsy, autism, and schizophrenia.

描述（由申请方提供）：常染色体隐性遗传性原发性小头畸形（MCPH）是一种遗传和临床异质性疾病，定义为出生时头围减小。患者通常有广泛的神经系统问题，包括精神发育迟滞、局灶性或全身性癫痫发作、多动和注意力缺陷障碍。脑体积的减少而没有主要的结构异常最有可能源于神经发生和/或神经元迁移的原发性缺陷。八个MCPH基因中的五个在细胞周期的全部或部分过程中定位于中心体。体外研究提供的证据表明，这些基因在基本的中心体功能，如细胞周期调控中发挥作用。尽管如此，MCPH在大脑发育中的机制仍然知之甚少。该项目的长期目标是描述MCPH基因在新皮质发育和疾病发病机制中的作用。目的是揭示MCPH基因对神经发生的分子和细胞控制，并确定中心体蛋白如何调节分裂模式（对称或不对称），神经元迁移和分化。我们实验室和其他实验室最近的研究表明，放射状胶质细胞是神经元祖细胞的主要群体。它们不对称地分裂以自我更新并产生皮层神经元。不对称中心体遗传被认为调节胚胎小鼠新皮层中自我更新祖细胞与分化后代的差异行为。果蝇中心体缺陷不会显著干扰大多数体细胞的有丝分裂，但幼虫成神经细胞的不对称分裂明显中断，强调了中心体行为对祖细胞不对称细胞分裂和子细胞命运决定的特殊意义。此外，中心体是微管的主要锚，使分化中的神经元能够启动和延伸轴突，这是神经元分化的关键过程。基于这些观察，本申请的中心假设是MCPH基因控制发育中的皮层中的神经发生、神经元迁移和分化。在强有力的初步数据的指导下，这一假设将通过追求四个具体目标来检验：1）确定MCPH基因调节放射状胶质细胞分裂的分子和细胞机制：2）探索MCPH基因在调节母亲与女儿中心体的不对称遗传和女儿细胞命运中的功能; 3）确定MCPH基因在调节发育中皮质神经元迁移和分化中的功能;和4）使用患者诱导的多能干（iPS）细胞验证小鼠中的发现与人MCPH发病机制的相关性。通过包括高时间延时成像和分子遗传技术在内的创新方法，拟议的研究将为MCPH的发病机制提供新的见解，并扩大我们对大脑发育的了解。此外，这项研究的结果可能揭示了许多与皮质功能相关的神经和精神疾病的病因学机制。 公共卫生相关性：本研究探讨了人类小头畸形的分子和细胞机制，小头畸形是一种重要的神经发育障碍，但研究不足。了解小头畸形如何发展不仅对更深入地了解大脑发育很重要，而且对我们理解和潜在治疗由大脑皮层发育缺陷引起的各种其他神经发育障碍也很重要，包括精神发育迟滞，癫痫，自闭症和精神分裂症。