Proliferative asymmetry in the neural stem cell lineage established by asymmetric cell division

由不对称细胞分裂建立的神经干细胞谱系的增殖不对称性

• 批准号: 10664431
• 负责人: Bryce LaFoya
• 金额: $ 12.5万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-07 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664431
• 关键词: Animal Model; Animals; Apical; Biological Assay; Brain; Cell Cycle; Cell Lineage; Cell Proliferation; Cell division; Cells; Central Nervous System; Data; Daughter; Defect; Development; Disease; Drosophila genus; Educational process of instructing; Ensure; Failure; Goals; Grant; Growth; Inherited; Invertebrates; Laboratories; Learning; Lipids; Measures; Mediating; Mentors; Modeling; Molecular; Mothers; Neurons; Organ; PIK3CG gene; Pathway interactions; Proliferating; Proliferation Marker; Proteins; Regulation; Research; Role; Running; S-Phase Fraction; Siblings; Side; Specific qualifier value; System; Testing; Tissues; Training; Training Activity; Vertebrates; Work; Writing; Zebrafish; cell cortex; cell type; daughter cell; follow-up; improved; live cell imaging; member; nerve stem cell; neurogenesis; prevent; programs; repaired; screening; segregation; skills; stem cell division; stem cell proliferation; stem cell therapy; stem cells; tissue repair; training opportunity; tumorigenesis

ABSTRACT In the proposed work, I will be investigating how neural stem cells establish ‘proliferative asymmetries’, which are responsible for precisely controlling the development and repair of the central nervous system. During development and tissue repair, stem cells are triggered to proliferate. While proliferation is necessary, it must be precise to prevent overgrowth that can lead to tumorigenesis. As neural stem cells proliferate, they commonly divide asymmetrically. The ability to undergo asymmetric cell division is a highly conserved feature of neural stem cells across all animals. Asymmetric cell division produces one daughter cell that retains the neural stem cell identity, and one daughter cell which takes on a neuron-producing progenitor cell identity. A key difference between these two daughter cells is that the stem cell will rapidly reenter the cell cycle and divide again, while the progenitor cell will divide much more slowly or stop dividing all together. This proliferative asymmetry ensures that the proper number of neurons are produced, and its disruption leads to defects in neurogenesis. The molecular basis for this proliferative asymmetry mostly unknown. I will focus my independent research program around the mechanisms which establish this proliferative asymmetry. I hypothesize that this proliferative asymmetry is established by the differential inheritance of proliferation promoting factors during asymmetric cell division. I plan to learn how neural stem cells generate proliferative asymmetries in both invertebrates and vertebrates, through the use of Drosophila and zebrafish animal models. Studying both animal models will allow me to identify conserved and divergent modes of generating proliferative asymmetries in neural stem cells, while also providing me with new training opportunities. Both animal models are highly amenable to live cell imaging of neural stem cells in developing brains. In Aim 1, I will screening for proliferation regulators which are polarized in the mother neural stem cell. In Aim 2, I will determine how polarized proliferative regulators contribute to proliferative asymmetries between sibling cells. In Aim 3, I will determine how PAR polarity proteins regulate the PI3K proliferation pathway. Through my initial screening, I have already discovered one promising candidate that appears to mediate the proliferative asymmetry in the neural stem cell lineage, the lipid PIP3. PIP3 is transiently produced by the mother neural stem cell just before division, becomes polarized to one side of the cell, and gets inherited by the daughter cell which retains the neural stem cell identity. Discovering how PIP3 and other factors establish proliferative asymmetries during asymmetric cell division will advance our understanding of how neural stem cells mediate development and tissue repair. Through training activities aimed at improving my skills in grant writing, scientific teaching, and mentoring, I will be better prepared to run my own laboratory. The scientific discoveries and training this proposal will facilitate, will be foundational to building my independent research program.

抽象的 在拟议的工作中，我将研究神经干细胞如何建立“增殖性不对称”，这 负责精确控制中枢神经系统的发展和修复。期间 发育和组织修复，干细胞被触发以增殖。虽然需要扩散，但必须是 精确以防止过度生长，可能导致肿瘤发生。随着神经干细胞的增殖，它们通常 不对称分裂。进行不对称细胞分裂的能力是神经元的高度保守特征 干细胞遍布所有动物。不对称细胞分裂产生一个保留神经茎的子细胞 细胞同一性和一个子细胞，具有神经产生的祖细胞身份。关键区别 在这两个子细胞之间，干细胞将迅速重新进入细胞周期并再次分裂，而 祖细胞将更慢地分裂或停止将所有分裂在一起。这种扩散不对称确保 产生适当数量的神经元，其破坏会导致神经发生缺陷。 这种增殖不对称的分子基础主要未知。我将集中我的独立研究计划 围绕建立这种增殖不对称的机制。我假设这激增 不对称是通过在不对称细胞中增殖因子的差异遗传来确定的 分配。我计划学习神经干细胞如何在无脊椎动物和 脊椎动物通过使用果蝇和斑马鱼动物模型。研究两种动物模型将允许 我确定在神经干细胞中产生不对称性增殖的保守和不同模式，而 还为我提供了新的培训机会。两种动物模型都可以高度适合活细胞成像 发育中的神经干细胞的神经干细胞。在AIM 1中，我将筛选为极化的增殖调节器 在AIM 2中，我将确定两极分化的扩散剂如何贡献 同胞细胞之间的不对称性。在AIM 3中，我将确定Parlity蛋白如何调节 PI3K增殖途径。通过最初的筛选，我已经发现了一个有前途的候选人 这似乎可以介导神经干细胞谱系中脂质PIP3中的增殖不对称性。 PIP3是 在分裂之前由母神经干细胞暂时产生 细胞，并由保留神经干细胞身份的子细胞遗传。发现pip3 和其他因素在不对称细胞分裂期间产生增殖的不对称性将推进我们的 了解神经干细胞如何发育和组织修复。通过针对的培训活动 在提高我的赠款写作，科学教学和心理技能方面，我将为自己准备好自己的能力 实验室。该提案将有助于科学发现和培训，将是建立我的基础 独立研究计划。