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: 8640218
• 负责人: NOELLE D DWYER
• 金额: $ 34.22万
• 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/8640218
• 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）：极化神经干细胞在发育过程中的精确时间分裂产生各种祖细胞、神经元细胞和神经胶质细胞类型的机制仍然是生物学和医学中最引人注目的谜团之一。这些细胞如何分裂产生两个具有对称或不对称命运的子细胞，同时仍然保持极性和上皮结构，尽管取得了很大进展，但仍不清楚。胞质分裂，细胞质和膜成分的实际分配，很少在神经干细胞中直接研究。本申请的目的是直接研究和干扰哺乳动物神经干细胞的胞质分裂，包括体内和体外。核心假设是，胞质分裂机制不同的早期增殖和后来的神经原性分裂阶段，积极促进适当的区域和层结构的大脑皮层的产生。我们将通过三个具体目标来检验这一假设：1）表征和扰动不同发育阶段的皮质神经祖细胞中胞质分裂的空间和时间参数，2）将中间体遗传模式与对称和不对称命运相关联，并测试实验性增加中间体保留的命运后果，和3）阐明当细胞质分裂在发育的早期或晚期被特异性破坏时产生的表型。我们的长期目标是阐明在发育过程中不同祖细胞类型的细胞分裂机制的特定改变如何导致大脑大小和结构的变化，畸形或其他疾病。拟议的研究的贡献，预计将是一个创新的方法和工具的基础，用于研究细胞质分裂在正常和异常的大脑发育，以及更详细地了解细胞动力学结构如何分区顶端组件在神经祖细胞。这些贡献将是显着的，因为他们可能会发现新的机制，有助于差异的命运决定因素分离神经干细胞更新或神经发生，并预测人脑的表型，可能会出现从全球或本地化的胞质分裂缺陷。