Genetic and Molecular Studies of Neurogenesis

神经发生的遗传和分子研究

• 批准号: 7809004
• 负责人: Chris Q Doe
• 金额: $ 0.93万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2009-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7809004
• 关键词: Address; Animal Model; Applications Grants; Axon; Behavior; Behavior Disorders; Biological Assay; Biological Models; Castor; Cell Cycle; Cognition; Congenital Abnormality; DNA; Defect; Development; Drosophila genus; Embryo; Funding; Gene Expression; Gene Targeting; Generations; Genes; Genetic; Genetic Screening; Genetic Transcription; Goals; Grant; Human; Investigation; Lead; Learning; Malignant Neoplasms; Mammals; Mitotic; Molecular; Molecular Genetics; Movement; Nervous system structure; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neurons; Organism; Pattern; Pattern Formation; Perception; Phenotype; Platelet Factor 4; Production; Regulation; Research Personnel; Role; Series; Specific qualifier value; Testing; Time; To specify; Trans-Activators; Transcription Coactivator; base; cell type; clinically relevant; design; insight; mutant; nerve stem cell; neuroblast; neurogenesis; novel; pluripotency; programs; relating to nervous system; research study; tool; transcription factor

The human CMS contains a diversity of neurons and glia that regulate movement, perception, cognition, and overall behavior. Understanding how neuronal diversity is generated is clinically relevant for learning how to manipulate neural stem cells to generate needed cell types on demand, for recognizing the primary defect in neurodegenerative diseases, nervous system cancers, or for understanding behavioral disorders. Drosophila and mammals share a high degree of conservation in the mechanisms regulating neurogenesis, so we are using Drosophila as a model system for understanding how neural diversity is generated. The generation of neuronal and glial diversity requires the production of the appropriate cell types at the right place (spatial patterning) and at the right time (temporal patterning). Disruption of either spatial or temporal patterning can lead to embryonic lethality or birth defects. While the mechanisms regulating spatial pattern formation are well studied, relatively little is known about how neurons and glia are generated at specific times during CMS development. We and others have shown that four transcription factors are sequentially expressed in embryonic neuroblasts (Hunchback, Kruppel, Pdm1/2, and Castor). We have shown that Hunchback and Kruppel are necessary and sufficient for specifying "temporal identity" in several neuroblast lineages; for example, hunchback mutants lack the first-born neurons whereas extended hunchback expression leads to a reiteration of first-born neurons at the expense of later-born neurons. Major questions that we will address in this grant proposal are:(1) What are the transcriptional targets of Hunchback in the CMS? (2) What is the function of the later genes in the series, Pdm1/2 and Cas? (3) What is the "timer" that regulates the sequential expression of these four factors? (4) Can we identify additional genes that regulate temporal identity? These questions are relatively difficult to address in mammals, but over the last two decades it has become clear that model organisms such as Drosophila can be used to identify molecules and mechanisms important for mammalian neurogenesis. Thus, we propose to continue our investigation of temporal patterning in the Drosophila CMS,with the goal of providing insight into the mechanisms regulating temporal patterning during mammalian neurogenesis.

人类 CMS 包含调节运动的多种神经元和神经胶质细胞， 知觉、认知和整体行为。了解神经元多样性是如何产生的 与学习如何操纵神经干细胞生成所需的细胞类型具有临床相关性 需求，识别神经退行性疾病、神经系统的主要缺陷 癌症，或了解行为障碍。果蝇和哺乳动物有很高的共同点 调节神经发生机制的保守性，因此我们使用果蝇作为模型 用于理解神经多样性如何产生的系统。 神经元和神经胶质多样性的产生需要产生适当的细胞 在正确的地点（空间模式）和正确的时间（时间模式）打字。扰乱 空间或时间模式都可能导致胚胎死亡或出生缺陷。虽然 调节空间格局形成的机制已得到充分研究，但对于如何调节空间格局形成的机制知之甚少 神经元和神经胶质细胞在 CMS 发育过程中的特定时间生成。我们和其他人有 研究表明四种转录因子在胚胎神经母细胞中依次表达 （驼背、Kruppel、Pdm1/2 和 Castor）。我们已经证明 Hunchback 和 Kruppel 是 对于指定几个神经母细胞谱系中的“时间同一性”是必要和充分的；为了 例如，驼背突变体缺乏最初出生的神经元，而延长驼背表达 导致第一个产生的神经元的重复，而牺牲后来产生的神经元。 我们将在本拨款提案中解决的主要问题是：（1）什么是 Hunchback 在 CMS 中的转录目标？ (2) 后期基因的功能是什么？ 系列，Pdm1/2 和 Cas？ (3) 调节这些顺序表达的“定时器”是什么 四个因素？ (4) 我们能否鉴定出调节时间同一性的其他基因？这些问题 在哺乳动物中相对难以解决，但在过去的二十年里，人们已经清楚地知道 果蝇等模型生物可用于识别重要的分子和机制 用于哺乳动物神经发生。因此，我们建议继续研究时间模式 在果蝇 CMS 中，目的是深入了解调节时间的机制 哺乳动物神经发生过程中的模式。