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：
10808457
负责人：
Su Guo
金额：
$ 8.5万
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/10808457
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 Cytoplasm 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 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 Role Shapes Signal Transduction Specific qualifier value 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 superresolution microscopy 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.

项目概要不对称细胞分裂（ACD）在发育过程中的命运规范和形态发生中起着至关重要的作用。这个过程对于成年期的组织稳态和修复也至关重要。 ACD 失调导致发育/智力障碍和肿瘤发生，因此了解潜在的细胞至关重要和分子机制。 ACD 的一个关键方面是细胞极性的建立。无脊椎动物系统的研究已确定了重要的皮质极性调节因子，确保命运决定因素正确分为两个子细胞。这些研究进一步揭示了不同的蛋白质复合物如何建立和维持其皮质极性互反。尽管取得了这些进展，皮质定位蛋白如何极化非皮质分布式细胞命运决定因素尚不清楚。对脊椎动物系统的研究已经开始揭示对这些进化上保守的极性调节器的功能有了新的见解。放射状胶质祖细胞（RGP）是主要的脊椎动物神经干细胞（NSC），代表了一种模型细胞类型，因为它们主要在活跃的神经发生过程中进行 ACD 以平衡自我更新和分化。我们之前的工作表明在胚胎斑马鱼前脑 RGP 中，关键的皮质极性调节因子 Par-3 对于建立不对称至关重要子细胞中的Notch信号传导活动。目前尚不清楚 Par-3 是如何建立这种不对称性的。最近，据我们所知，我们首次发现 Par-3 存在于细胞质中，并且与含有 Notch 配体的内体上的动力蛋白运动复合体结合。 Par-3 和动力蛋白一起母体 RGP 需要将含有 Notch 配体的内体定向转运至自身更新女儿。此外，我们发现皮质 Par-3 结构域从间期的顶端向有丝分裂期间的后部，以与沿前后胚胎轴的细胞分裂方向对齐。在此应用中，我们希望基于这些新发现来解决以下问题：1）如何 Par-3 是否与动力蛋白一起作用来指导含有 Notch 配体的内体的极化动力学？ 2）皮质和细胞质 Par-3 之间的动态关系是什么？ 3）什么机制重建 Par-3 极性轴从间期的顶端基底到有丝分裂期间的前后？我们的中央假设内在和外在机制都可以重塑 Par-3 皮质极性；这个皮质然后极性建立了 Par-3 的极化细胞质梯度，这反过来又直接促进内体通过激活动力蛋白进行动力学。拟议的工作预计将对不对称分裂和神经干产生重要的新见解脊椎动物大脑发育过程中的细胞命运调控。这些发现应该会产生积极影响揭示基本原理，为阐明疾病病因和激发新的研究奠定基础治疗的发展。