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

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、神经元和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，尽管取得了许多进展，但仍不清楚。在神经干细胞中，胞质分裂，即细胞质和膜组分的实际分配，很少被直接研究。这一特殊应用的目的是在体内和体外直接研究和干扰哺乳动物神经干细胞的细胞分裂。核心假设是细胞分裂机制在早期增殖和后期神经原性分裂阶段不同，积极地促进了大脑皮层适当面积和层结构的产生。我们将通过三个具体目标来验证这一假设：1)表征和干扰皮层神经祖细胞在不同发育阶段的细胞分裂的时空参数；2)将中体遗传模式与对称和非对称命运联系起来，并测试实验增加中体保留的命运后果；3)阐明细胞分裂在发育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发育过程中不同祖细胞类型的细胞分裂机制的特异性改变如何导致大脑大小和结构、畸形或其他疾病的变化。本文的研究成果将为研究正常和异常大脑发育中的细胞动力学提供创新的方法和工具，并为更详细地了解细胞动力学结构如何划分神经祖细胞的顶端成分奠定基础。这些贡献将是重要的，因为它们可能揭示有助于神经干细胞更新或神经发生的不同命运决定因素分离的新机制，并对可能由细胞分裂的全局或局部缺陷引起的人类大脑表型做出预测。

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.