Genetic and Molecular Studies of Neurogenesis

人类的CMS包含多种神经元和神经胶质细胞来调节运动， 感知、认知和整体行为。了解神经元多样性是如何产生的 临床上与学习如何操纵神经干细胞以产生所需的细胞类型有关 识别神经退行性疾病、神经系统的原发缺陷的需求 癌症，或理解行为障碍。果蝇和哺乳动物有很高的共性 在调节神经发生的机制中的保守性，所以我们用果蝇作为一个模型 用于理解神经多样性是如何产生的系统。 神经元和神经胶质细胞多样性的产生需要产生适当的细胞。 在正确的位置(空间图案)和正确的时间(时间图案)打字。中断 无论是空间模式还是时间模式都可能导致胚胎死亡或出生缺陷。而当 调控空间格局形成的机制得到了很好的研究，但对如何形成空间格局知之甚少 神经元和神经胶质细胞是在CMS发育的特定时间产生的。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顺序表达 (驼背、Kruppel、Pdm1/2和Castor)。我们已经证明了驼背和克鲁佩尔 在几种神经母细胞系中指定“时间同一性”的充要条件； 例如，驼背突变体缺乏最初出生的神经元，而延长的驼背表达 导致了以后生神经元为代价的先天神经元的反复出现。 我们将在这项拨款建议中解决的主要问题是：(1)什么是 驼背基因在细胞质雄性不育中的转录靶点？(2)后期基因在不育系中的作用 系列、Pdm1/2和Cas？(3)调控这些基因顺序表达的“定时器”是什么 四个因素？(4)我们能识别出调节时间同一性的其他基因吗？这些问题 在哺乳动物身上相对较难解决，但在过去的二十年里，情况变得很明显 果蝇等模式生物可以用来识别重要的分子和机制 用于哺乳动物的神经发生。因此，我们建议继续我们对时间模式的研究 在果蝇CMS中，目的是提供对时间调节机制的洞察 哺乳动物神经发生过程中的模式。

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.