Asymmetric Cell Division in Vertebrate Brain Development

 描述（由申请人提供）：祖细胞/干细胞的不对称分裂在发育期间的细胞命运特化和组织形态发生中起重要作用。这一过程对于成年期的组织稳态和修复也至关重要。由于不对称分裂的失调可导致各种发育和智力障碍，因此了解潜在的细胞和分子机制至关重要。 在无脊椎动物系统的研究已经确定了重要的皮质极性调节，确保正确的分离到两个子细胞的命运决定因素。与这些进展相比，对脊椎动物不对称分裂的调控和随后的子代命运选择的了解要少得多。放射状胶质细胞（RG）祖细胞是脊椎动物脑中主要的神经干细胞（NSCs），其分裂不对称以平衡自我更新和分化。虽然Par-3复合体不对称地定位于分裂RG的顶侧，但RG分裂平面在很大程度上垂直于新月体，导致两个子代都遗传Par-3复合体。因此，Par复合物如何在这种条件下产生不同的子细胞命运？ 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。我们将测试的核心假设，皮质极性建立中心体不对称，以调节不对称的子细胞的命运在脊椎动物RG祖细胞。创新的方法和技术，包括SIM和STORM显微镜，体内延时成像和生化方法（如BioID）将被用来测试这一假设。 这项工作的预期成果是对脊椎动物发育过程中的不对称分裂和干细胞命运的重要新见解。这些发现将对揭示基本原理，阐明疾病病因和刺激新的治疗方法的发展奠定基础产生积极的影响。

 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.