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“增殖不对称”，这 负责精确控制中枢神经系统的发育和修复。 发育和组织修复，干细胞被触发增殖，虽然增殖是必要的，但它必须是。 精确地防止可能导致肿瘤发生的过度生长。随着神经干细胞的增殖，它们通常会发生。 不对称细胞分裂的能力是神经细胞高度保守的特征。 所有动物的干细胞不对称细胞分裂产生一个保留神经干的子细胞。 细胞身份，以及具有产生神经元的祖细胞身份的一个子细胞，这是一个关键的区别。 这两个子细胞之间的区别在于，干细胞会迅速重新进入细胞周期并再次分裂，而 这种增殖不对称性确保了祖细胞的分裂速度会慢得多或完全停止分裂。 产生适当数量的神经元，其破坏会导致神经发生缺陷。 这种增殖不对称性的分子基础大多未知，我将重点关注我的独立研究计划。 围绕建立这种增殖不对称的机制。 不对称性是由不对称细胞过程中增殖促进因子的差异遗传决定的 我计划了解神经干细胞如何在无脊椎动物和哺乳动物中产生增殖不对称性。 脊椎动物，通过使用果蝇和斑马鱼动物模型将允许研究这两种动物模型。 我识别神经干细胞中产生增殖不对称性的保守和发散模式，同时 也为我提供了新的培训机会，这两种动物模型都非常适合活细胞成像。 在目标 1 中，我将筛选极化的增殖调节因子。 在目标 2 中，我将确定极化增殖调节因子如何促进母体神经干细胞的生长。 在目标 3 中，我将确定 PAR 极性蛋白如何调节兄弟细胞之间的增殖不对称性。 通过我的初步筛选，我已经发现了一个有希望的候选者。 脂质 PIP3 似乎介导神经干细胞谱系的增殖不对称性。 由母体神经干细胞在分裂前短暂产生，极化到神经干细胞的一侧 细胞，并由保留神经干细胞身份的子细胞继承。 和其他因素在不对称细胞分裂过程中建立增殖不对称将促进我们的 通过旨在训练的活动了解神经干细胞如何介导发育和组织修复。 在提高我在资助写作、科学教学和指导方面的技能时，我将为自己的管理做好更好的准备 该提案将促进科学发现和培训，并将成为建设我的实验室的基础。 独立研究计划。