Asymmetric Cell Division in Vertebrate Brain Development

 描述(申请人提供)：祖细胞/干细胞的不对称分裂在细胞命运指定和发育过程中的组织形态发生中起着重要作用。这一过程对成年后的组织动态平衡和修复也至关重要。由于不对称分裂的异常调节可导致各种发育和智力障碍，了解其潜在的细胞和分子机制至关重要。对无脊椎动物系统的研究已经确定了重要的皮质极性调节因子，它们确保命运决定因素适当地分离到两个子细胞中。与这些进展相比，人们对脊椎动物不对称分裂的调控以及随后的子代命运选择的了解要少得多。放射状胶质细胞(RG)前体细胞是脊椎动物大脑中主要的神经干细胞(NSCs)，它们不对称分裂以平衡自我更新和分化。虽然PAR-3复合体不对称地位于分裂RGS的顶侧，但RG裂解面基本上垂直于新月体，导致两个子代都继承了PAR-3复合体。因此，在这样的条件下，PAR复合体是如何产生不同的子细胞命运的？在这个应用中，我们建议使用斑马鱼发育中的大脑作为模型来解决这个问题。我们将验证中央假设，即皮质极性建立中心体不对称性，以调节脊椎动物RG前体细胞的不对称子细胞命运。创新的方法和技术，包括SIM和STORM显微镜，活体时间推移成像，以及生化方法(如BioID)将被用来检验这一假说。这项拟议工作的预期结果是对脊椎动物发育过程中不对称分裂和干细胞命运的重大新见解。这些发现将对揭示基本原理产生积极影响，并为阐明疾病病因和刺激新的治疗开发奠定基础。

 DESCRIPTION (provided by applicant): Asymmetric division of progenitor/stem cells plays an important role in cell fate specification and tissue morphogenesis during development. This process is also critical for tissue homeostasis and repair in adulthood. Since dys-regulation of asymmetric division can lead to a variety of developmental and intellectual disabilities, it is critical to understand the underlying cellular and molecular mechanisms. Studies in invertebrate systems have identified important cortical polarity regulators, which ensure proper segregation of fate determinants into two daughter cells. Compared to these advances, much less is understood about the regulation of asymmetric division and subsequent daughter fate choice in vertebrates. Radial glia (RG) progenitors, the principal neural stem cells (NSCs) in the vertebrate brain, divide asymmetrically to balance self-renewal and differentiation. Although the Par-3 complex is asymmetrically localized to the apical side of dividing RGs, the RG cleavage plane is largely perpendicular to the crescent, resulting in the inheritance of Par-3 complex by both daughters. Therefore, how do the Par complexes generate distinct daughter cell fate under such conditions? In this application, we propose to use the zebrafish developing brain as a model to address this question. We will test the central hypothesis that cortical polarity establishes centrosome asymmetry to regulate asymmetric daughter cell fate in vertebrate RG progenitors. Innovative methods and techniques, including SIM and STORM microscopy, in vivo time-lapse imaging, and biochemical approaches (e.g. BioID) will be employed to test this hypothesis. The expected outcome of the proposed work is significant new insights into asymmetric division and stem cell fate during vertebrate development. These findings should have a positive impact on revealing fundamental principles, and laying groundwork for elucidating disease etiology and stimulating new therapeutic development.