Roles of Cytokinesis in Polarized Neural Stem Cell Divisions and Brain Growth

细胞分裂在极化神经干细胞分裂和大脑生长中的作用

• 批准号: 8500876
• 负责人: NOELLE D DWYER
• 金额: $ 34.56万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8500876
• 关键词: Acute; Address; Affect; Apical; Architecture; Area; Autistic Disorder; Biology; Brain; Cell division; Cell membrane; Cell model; Cells; Centrosome; Cerebral cortex; Classification; Cytokinesis; Daughter; Defect; Development; Developmental Biology; Diagnosis; Disease; Epilepsy; Epithelial; Event; Excision; Foundations; Generations; Genes; Genetic; Genetic Screening; Goals; Growth; Human; In Vitro; Individual; Inheritance Patterns; Knowledge; Lead; Medicine; Methods; Microcephaly; Mission; Modeling; Mothers; Mutant Strains Mice; Mutation; National Institute of Neurological Disorders and Stroke; Nervous System Trauma; Neurodevelopmental Disorder; Neuroglia; Neurologic; Neurons; Outcome; Phase; Phenotype; Play; Positioning Attribute; Process; Public Health; Regulation; Research; Role; Side; Sister; Specific qualifier value; Speed; Staging; Structure; Surface; System; Testing; Therapeutic; Thick; Time; Tissues; Variant; Work; apical membrane; base; brain malformation; brain size; cell type; in vivo; innovation; malformation; mutant; nerve stem cell; nervous system disorder; neurogenesis; novel; progenitor; public health relevance; relating to nervous system; research study; segregation; spatial relationship; stem cell division; tool; translational medicine

DESCRIPTION (provided by applicant): The mechanisms by which polarized neural stem cells divide to produce various progenitor, neuronal, and glial cell types at precise times during development remain among the most compelling mysteries in biology and medicine. How these cells split to produce two daughters with symmetric or asymmetric fates, while still maintaining polarity and epithelial structure, remains unclear despite much progress. Cytokinesis, the actual partitioning of cytoplasmic and membrane components, has rarely been directly studied in neural stem cells. The objective of this particular application is to directly study and perturb cytokinesis in mammalian neural stem cells, both in vivo and in vitro. The central hypothesis is that cytokinesis mechanisms differ between early proliferative and later neurogenic division phases, contributing actively to the generation of a cerebral cortex of the proper area and layer structure. We will test this hypothesis through three Specific Aims: 1) characterize and perturb spatial and temporal parameters of cytokinesis in cortical neural progenitors at different stages of development, 2) correlate midbody inheritance patterns with symmetric and asymmetric fates, and test the fate consequences of experimentally increasing midbody retention, and 3) elucidate phenotypes produced when cytokinesis is specifically disrupted during early or late stages of development. Our long-term goal is to elucidate how specific alterations in cell division mechanisms in different progenitor types during development can lead to variations in brain size and structure, malformations, or other disorders. The contributions of the proposed research are expected to be a foundation of innovative approaches and tools for studying cytokinesis in normal and abnormal brain development, and a more detailed understanding of how cytokinetic structures partition apical components in neural progenitors. These contributions will be significant because they may uncover novel mechanisms that contribute to differential fate determinant segregation for neural stem cell renewal or neurogenesis, and make predictions for human brain phenotypes that may arise from global or localized defects in cytokinesis.

描述（由申请人提供）：在发育过程中，在精确时期，极化神经干细胞分裂以产生各种祖细胞，神经元和神经胶质细胞类型的机制仍然是生物学和医学上最引人注目的奥秘之一。这些细胞如何分裂以产生两个具有对称或不对称命运的女儿，同时仍保持极性和上皮结构，尽管进展很大，但仍不清楚。细胞因子是细胞质和膜成分的实际分区，很少直接研究在神经干细胞中。该特定应用的目的是在体内和体外直接研究和扰动细胞因子。中心假设是，早期增殖和后来的神经源性分裂阶段的细胞因子机制有所不同，从而积极地产生了适当区域和层结构的大脑皮层。我们将通过三个具体目的通过三个特定目的来检验这一假设：1）在不同发展阶段在皮质神经祖细胞中的细胞因子的空间和时间参数表征和扰动，2）将中体遗传模式与对称和非对称融合的相关性和非对称性融合，并在实验上的产生时，并在实验上的产生效果，并在实验上的产生效果，并指出特定的IS 3）精华量。在开发的早期或晚期中受到破坏。我们的长期目标是阐明在发育过程中不同祖细胞类型中细胞分裂机制的特定变化如何导致脑大小和结构，畸形或其他疾病的变化。拟议的研究的贡献预计将是研究正常和异常脑发育中细胞因子的创新方法和工具的基础，并且对细胞因子结构如何在神经祖细胞中分配顶端成分的详细了解。这些贡献将是重要的，因为它们可能会发现新的机制，这些机制有助于神经干细胞更新或神经发生的差异命运决定因素分离，并对细胞因子中的全球或局部缺陷产生的人脑表型进行预测。