Abscission regulation of corticogenesis

皮质生成的脱落调节

• 批准号: 10544030
• 负责人: NOELLE D DWYER
• 金额: $ 41.28万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10544030
• 关键词: Affect; Age; Apical; Apoptosis; Area; Biological; Biological Assay; Biology; Brain; Cancer cell line; Cell Cycle; Cell Line; Cell Maintenance; Cell Polarity; Cell division; Cells; Cellular Assay; Cilia; Complex; Coupling; Data; Daughter; Defect; Development; Dissociation; Epilepsy; Excision; Gene Deletion; Gene Mutation; Genes; Genetic; Geometry; Health; Image; In Vitro; Individual; Knowledge; Lead; Link; Long-Term Effects; Malignant Neoplasms; Mediating; Methods; Microcephaly; Microtubules; Mission; Molecular; Morphology; Mothers; Mutant Strains Mice; Mutation; National Institute of Neurological Disorders and Stroke; Neurodevelopmental Disorder; Neurons; Organ; Organelles; Outcome; Paper; Pathway interactions; Phenotype; Positioning Attribute; Probability; Process; Public Health; Regulation; Reporter; Research; Signal Pathway; Signal Transduction; Structure; Surface; System; TP53 gene; Testing; Time; Tissues; Ventricular; WNT Signaling Pathway; apical membrane; autism spectrum disorder; beta catenin; brain malformation; brain size; candidate identification; cell type; cilium biogenesis; daughter cell; experimental study; in vivo; innovation; mosaic analysis; mosaic loss; mutant; nerve stem cell; nervous system disorder; neurodevelopment; neuroregulation; novel; stem; stem cell division; stem cell expansion; stem cells; stemness; tool; transcriptome sequencing; transmission process

Abstract: In order for the brain to develop with proper size and structure, neural stem cells (NSCs) at early ages must make proliferative divisions and maintain their stemness to expand the stem cell pool, but then switch to undergo neurogenic divisions at the correct time to create neurons. However, the mechanism of this fate choice from remaining an NSC early on, to later choosing to exit the cell cycle and become a neuron, is still poorly understood. The last step of cell division is abscission, which severs the daughter from the mother cell. Abscission occurs during the time when the fate decision is made, and at the apical membrane, where many fate signals are located. We developed methods and tools to quantitatively analyze abscission in cortical NSCs, in vivo and in vitro. We found that abscission is not simply necessary to cut cells apart and keep them alive. Rather, we made the surprising discovery that both abscission duration and remnants of abscission (midbody remnants) are developmentally regulated, changing as development proceeds. Furthermore, we found that a small-brained mouse mutant with altered abscission duration has a reduced proportion of proliferative NSC divisions. These data led to our central hypothesis that changes in abscission duration and midbody remnant persistence can shift NSC daughter cells fate choices as development proceeds. We will test this hypothesis through the use of innovative genetic and cell biological approaches, on single NSC divisions and whole tissue analyses. We will utilize two mouse mutants that perturb abscission specifically, affecting duration and midbody remnants differentially. We will carry out three Specific Aims: 1) test whether abscission duration is correlated with daughter cell fate outcomes in vitro, 2) dissect the primary and secondary effects of dysregulated abscission on cortical NSC daughter cell fates, morphologies and lineage progression in vivo, and 3) investigate a candidate signaling mechanism at the apical membrane that could link abscission regulation to stem cell maintenance. The contributions of the proposed research will be to increase understanding of the fundamental question of how stem cells in developing tissues maintain high proliferative capacity early and then reduce it later in favor of differentiated daughter cell types. It will also elucidate how regulation of NSC divisions affect daughter cell fates, structures, and subsequent divisions. These contributions will be significant because they will reveal novel mechanisms and gene pathways that regulate how brain size and structure are controlled, and will elucidate how specific alterations in NSC division mechanisms during development can lead to brain malformations, or other neurodevelopment phenotypes.

摘要：为了使大脑发育成合适的大小和结构，早期的神经干细胞(NSCs) AGEs必须进行增殖分裂并保持其干性，以扩大干细胞库，但随后 在正确的时间切换到进行神经性分裂，以创造神经元。然而，这一机制 这个命运的选择，从早期的NSC，到后来选择退出细胞周期，成为 神经元，人们对此仍知之甚少。细胞分裂的最后一步是脱落，它将女儿与 母细胞。分离发生在命运决定的时间段，在顶端。 膜，许多命运信号所在的地方。我们开发了定量分析的方法和工具 在体内和体外，皮质神经干细胞的脱落。我们发现，脱落并不是切割细胞所必需的 分开，让他们活着。相反，我们有一个令人惊讶的发现，无论是脱落持续时间还是 脱落的残留物(中身残留物)是发育调节的，随着发育而变化。 收益。此外，我们还发现，小脑小鼠突变体的脱落持续时间发生了变化。 增生性NSC分裂的比例降低。这些数据导致了我们的核心假设，即 脱落持续时间和中体残留可以改变NSC子代细胞的命运选择 发展取得了进展。我们将通过使用创新的遗传学和细胞生物学来检验这一假说 方法，关于单个NSC分区和整个组织分析。我们将利用两个小鼠突变体 特别是扰动脱落，对持续时间和中体残留物的影响不同。我们将开展三项工作 具体目的：1)检测离体持续时间是否与子代细胞的体外结局相关；2) 解剖失调性脱落对皮质神经干细胞子代细胞命运的原发和继发影响， 在体内的形态和谱系进展，以及3)研究候选信号机制在 顶膜可以将脱落调节与干细胞维持联系起来。该基金会的贡献 拟议的研究将增加对干细胞如何在体内 发育中的组织早期保持高增殖能力，后来又降低，有利于分化 子代细胞类型。它还将阐明神经干细胞分裂的调节如何影响子代细胞的命运， 结构，以及随后的划分。这些贡献将是重要的，因为它们将揭示出 调节大脑大小和结构如何控制的机制和基因途径，并将阐明 在发育过程中神经干细胞分裂机制的具体变化如何导致大脑畸形，或者 其他神经发育表型。