Diversity Supplement

多样性补充

• 批准号: 10495125
• 负责人: Su Guo
• 金额: $ 3.92万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10495125
• 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

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.

项目摘要 不对称细胞分裂（ACD）在发育过程中在命运规范和形态发生中起关键作用。 这个过程对于成年后的组织稳态和修复也至关重要。 ACD的DYS调节导致 发育/智力残疾和肿瘤发生，使了解潜在的细胞至关重要 和分子机制。 ACD的一个关键方面是建立细胞极性。无脊椎动物系统的研究具有 确定了重要的皮质极性调节剂，以确保将命运决定因素适当地分解为两个 子细胞。这些研究进一步阐明了不同的蛋白质复合物如何建立和维持其 相互皮质极性。尽管有这些进展，但皮质局部蛋白质如何非皮质化偏振 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开始发现 对这些进化保守的极性调节剂功能的新见解。 radial胶质神经胶质祖细胞 （RGP），主脊椎动物神经干细胞（NSC），代表模型细胞类型，主要是它们 在主动神经发生过程中经历ACD，以平衡自我更新和分化。我们先前的工作表明 在胚胎斑马鱼前脑rgps中，关键皮质极性调节剂PAR-3对于建立不对称至关重要 儿子细胞中的Notch信号传导活性。第3杆如何建立不对称性仍然未知。 最近，据我们所知，我们第一次发现了par-3存在于细胞质中，并且 在含有Notch配体的内体上与Dynein Motor复合物相关联。在一起，三杆和动力蛋白 母亲RGP需要定向运输含有配体的内体 更新女儿。此外，我们发现皮质par-3结构域从相互作用的顶端转移 有丝分裂期间的后部，与沿前后胚胎轴的细胞分裂方向保持一致。 在此应用程序中，我们希望以这些新发现来解决以下问题：1） par-3是否与动力蛋白一起工作以直接含有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）哪些机制重建 在有丝分裂期间，在相间阶段到前后验的par-3极性轴？我们的中心 假设是固有和外在机制都起作用可重塑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，进而直接促进内体 激活动力蛋白的动力学。 预计拟议的工作将对不对称分裂和神经茎产生重大的新见解 脊椎动物脑发育过程中的细胞命运调节。这些发现应该对 揭示基本原理和为阐明疾病病因和刺激新的基础工作 治疗发展。