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Asymmetric Cell Division of Vertebrate Radial Glia Neural Progenitors

脊椎动物放射状胶质神经祖细胞的不对称细胞分裂

基本信息

批准号：
10231508
负责人：
Su Guo
金额：
$ 39.21万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10231508
关键词：
Address Adult Anaphase Anterior Apical Biochemical Biophysics Brain Brain Diseases Brain Neoplasms Cell Cycle Cell Fate Control Cell Polarity Cell division Cell model Cells Complex Coupled Cytosol Data Daughter Development Diagnosis Disease Dynein ATPase Embryo Endosomes Ensure Equilibrium Etiology Exhibits Homeostasis Human Image In Vitro Intellectual functioning disability Interphase Invertebrates Ligands Light Link Microscopy Microtubules Mitosis Mitotic Molecular Molecular Genetics Morphogenesis Mothers Motor Neurodevelopmental Disorder Neuroglia Phosphorylation Photobleaching Play Positioning Attribute Process Property Prosencephalon Proteins Public Health Radial Recovery Research Resolution Role Signal Transduction System Testing Time Tissues Work Zebrafish cell motility cell type daughter cell density genetic approach imaging genetics in vivo in vivo imaging insight nerve stem cell neurogenesis notch protein novel therapeutics planar cell polarity progenitor protein complex reconstruction repaired segregation self-renewal stem cell self renewal telophase therapeutic development tumorigenesis

项目摘要

PROJECT SUMMARY Asymmetric cell division (ACD) plays a critical role in fate specification and morphogenesis during development. This process is also crucial for tissue homeostasis and repair in adulthood. Dys-regulation of ACD results in developmental/intellectual disabilities and tumorigenesis, making it critical to understand the underlying cellular and molecular mechanisms. A critical aspect of ACD is the establishment of cell polarity. Studies in invertebrate systems have identified important cortical polarity regulators, which ensure proper segregation of fate determinants into two daughter cells. These studies further shed light on how distinct protein complexes establish and maintain their reciprocal cortical polarity. Despite these advances, how cortically localized proteins polarize non-cortically distributed cell fate determinants is not well understood. Research into vertebrate systems has begun to uncover new insights into the function of these evolutionarily conserved polarity regulators. Radial glia progenitors (RGPs), the principal vertebrate neural stem cells (NSCs), represent a model cell type as they predominantly undergo ACD during active neurogenesis to balance self-renewal and differentiation. Our prior work shows that in embryonic zebrafish forebrain RGPs, the key cortical polarity regulator Par-3 is critical to establish asymmetric Notch signaling activity in daughter cells. It remains unknown how Par-3 establishes such asymmetry. Recently, we uncover, for the first time to our knowledge, that Par-3 is present in the cytosol and associates with the dynein motor complex on Notch ligand-containing endosomes. Together, Par-3 and dynein are required in the mother RGP to directionally transport Notch ligand-containing endosomes to the self- renewing daughter. Additionally, we discover that cortical Par-3 domain shifts from apical at interphase toward posterior during mitosis, to align with cell division orientation along the anteroposterior embryonic axis. In this application, we wish to build upon these new findings to address the following questions: 1) how does Par-3 work together with dynein to direct polarized dynamics of Notch ligand-containing endosomes? 2) what is the dynamic relationship between cortical and cytoplasmic Par-3? 3) What mechanisms reconstruct the axis of Par-3 polarity from apicobasal during interphase to anterior-posterior during mitosis? Our central hypothesis is that both intrinsic and extrinsic mechanisms operate to reshape Par-3 cortical polarity; this cortical polarity then sets up a polarized cytoplasmic gradient of Par-3, which in turn directly facilitates endosome dynamics by activating dynein. The proposed work is expected to yield significant new insights into asymmetric division and neural stem cell fate regulation during vertebrate brain development. These findings should have a positive impact on revealing fundamental principles and laying groundwork for elucidating disease etiology and stimulating new therapeutic development.

项目总结