Developmental genetics of neural stem cells

神经干细胞的发育遗传学

• 批准号: 9765350
• 负责人: KRISHNA MOORTHI BHAT
• 金额: $ 29.9万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-16 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765350
• 关键词: 3' Untranslated Regions; Address; Alleles; Apoptosis; Automobile Driving; Biology; CCNE1 gene; Cell Cycle; Cell Cycle Regulation; Cell division; Cells; Chromosomes; Complex; DNA biosynthesis; Development; Drosophila genus; Entropy; Environment; Genes; Genetic; Grant; Length; Link; Malignant Neoplasms; Measures; Mediating; Messenger RNA; Monitor; Mutation; Nerve; Nervous system structure; Neurons; Nuclear; Organism; Organogenesis; Play; Process; Protein Family; Proteins; Regulation; Rest; Role; Somatic Cell; Specific qualifier value; System; Telomere Shortening; Testing; Thermodynamics; Time; To specify; Work; developmental genetics; fly; gain of function mutation; gene cloning; loss of function; mRNA Transcript Degradation; member; mutant; nerve stem cell; neuroblast; precursor cell; prevent; self-renewal; telomere; tool

Abstract In the Drosophila nerve cord, neuronal precursor cells called neuroblasts (NBs) undergo a variable number of self-renewing asymmetric divisions. At some point during development, these cells either become quiescent but re-enter cell cycle later, terminally divide into neurons, or undergo apoptosis. No one knows whether these precursors measure elapsed time or count the number of divisions before exiting the cell-cycle. In the fly nervous system, NBs differ in their division potential--the number of times they undergo division. NBs must decide to enter or exit from the cell cycle, but whether their read out is the time elapsed or a cell cycle count is unknown. Additionally, we do not know whether the mechanism(s) is regulated from within the cell or extrinsic to the cell. These are difficult questions to address. By examining different types of NBs, we hope to reveal genes and mechanisms that regulate the cell cycle entry and exit, and the division potential of NBs during development. During the course of our work on genetic regulation of asymmetric division of precursors, we isolated a mutation that caused additional divisions of precursor cells in many lineages in the nerve cord. We cloned the gene and found that it is a member of the T-box protein family. These proteins play important roles from development to cancer. Our studies on this gene, midline, led us to believe that it regulates precursor cell entry and exit from the cell-cycle. It appears to also play a role as part of a mechanism by partnering with Prospero. Thus, our specific aims are: 1) Determine the role of Mid in the cell cycle entry and exit by neuronal stem cells, 2) Determine the regulation of mid-expression, whether it is linked to the system that it regulates or originates outside of the cells it regulates, and 3) Determine if Mid partners with Prospero to specify the division potential of precursor cells. The cell cycle entry and exit by precursors and the regulation of their division potential are exceedingly difficult problems to study. Whether these regulatory mechanisms reside within the cell or extrinsic to cells, do cells measure the time elapsed, or is there a counting mechanism that determines/interacts with the cell cycle machinery, are all unknowns. Our aims are focused on exploring these issues using a powerful genetic system. By no means is this proposal only Mid or Pros-centric, these players are entry points to tackle the above problems in biology.

摘要 在果蝇神经索中，被称为神经母细胞(NBS)的神经元前体细胞经历了一个变量 自我更新的不对称划分的数量。在发育过程中的某个时刻，这些细胞 变得静止，但稍后重新进入细胞周期，最终分裂为神经元，或经历细胞凋亡。无名之辈 知道这些前兆是测量已用时间还是计算在退出 细胞周期。在苍蝇神经系统中，NBS的分裂潜力不同--它们经历的次数不同 组织。NBS必须决定进入或退出细胞周期，但他们的读数是经过的时间还是 细胞周期计数尚不清楚。另外，我们不知道这个机制(S)是否从 细胞内的或细胞外的。这些都是难以解决的问题。通过检查不同类型的 NBS，我们希望揭示调节细胞周期进出的基因和机制，以及 国家统计局在发展中的分工潜力。 在我们研究前体不对称分裂的遗传调控的过程中，我们分离出了一种 导致神经索许多谱系的前体细胞额外分裂的突变。我们 克隆了该基因，发现它是T-box蛋白家族的成员。这些蛋白质起着重要的作用。 从发育到癌症。我们对这种中线基因的研究使我们相信它调节前体细胞 进入和退出细胞周期。它似乎也发挥了作用，作为机制的一部分，通过与 普洛斯佩罗。因此，我们的具体目标是：1)通过以下方式确定Mid在细胞周期进入和退出中的作用 神经干细胞，2)确定中间表达的调节，是否与系统有关 它调节或起源于它调节的细胞之外，以及3)确定Mid是否与 Propero指定前体细胞的分裂潜力。 细胞周期前体的进出及其分裂潜能的调节是非常困难的。 要研究的问题。无论这些调节机制驻留在细胞内还是细胞外，细胞 测量经过的时间，或者是否有确定/与细胞周期相互作用的计数机制 机械，都是未知的。我们的目标是用一种强大的基因来探索这些问题 系统。这项建议绝不是只以中级或职业球员为中心，这些球员是解决 以上是生物学中的问题。