This research will reveal new molecular and cellular mechanisms that regulate neural stem cell self-renewal and differentiation. Since neural stem cells are responsible for generating the vast number of differentiated cell types in our brain, understanding how they might be regulated will have a broad impact on the understanding of human brain development and associated brain disorders.
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.