Development and function of hypothalamic Lhx6-positive neurons

项目摘要 下丘脑背外侧区的GABA能神经元在调节神经元的兴奋性和兴奋性中起重要作用。 睡眠/觉醒周期，但对控制其发展的分子机制知之甚少。我们有 最近发现LIM同源域转录因子Lhx 6对于群体的发育是必需的 促进睡眠的γ-氨基丁酸能神经元在下丘脑的齿状回。LHX 6是必不可少的， 在下丘脑中，Lhx 6在大多数端脑中间神经元的发育和迁移中表达， 不表达端脑Lhx 6阳性中间神经元标记物的更有限的神经元子集。的 Lhx 6在端脑和下丘脑神经元发育中的作用在几个重要方面不同。 Lhx 6在两个区域的表达受不同的转录因子调控。初步基因表达 分析已经确定了许多基因，它们是介导这些差异的强有力的候选者。在这 建议，我们的目标是确定指导下丘脑的规范和生存的分子机制， Lhx 6神经元。首先，我们将使用遗传学方法的组合，以确定转录调控 启动和维持下丘脑Lhx 6表达所需的网络，以及控制Lhx 6表达的网络。 Lhx 6阳性神经元的不同亚型的发育。接下来，我们将确定切向单元是否 迁移在促进睡眠的Lhx 6阳性神经元的定位中起着关键作用，并确定了 控制这个过程的分子机制。最后，我们将识别睡眠激活的分子亚型 Lhx 6阳性下丘脑神经元，并研究突变体如何破坏这些神经元的发育 导致睡眠/觉醒周期的调节改变。这将提供深入了解分子途径，控制 下丘脑神经回路的关键组成部分的组装，并可能确定治疗靶点， 治疗睡眠障碍。

Project Summary GABAergic neurons of the dorsolateral hypothalamus play an essential role in both the regulating the sleep/wake cycle, but little is known about the molecular mechanisms that control their development. We have recently found that the LIM homeodomain transcription factor Lhx6 is necessary for development of a population of sleep-promoting GABAergic neurons in the zona incerta in the hypothalamus. Lhx6 is essential for development and migration of most telencephalic interneurons, in the hypothalamus Lhx6 is expressed in a much more restricted subset of neurons that do not express markers of telencephalic Lhx6-positive interneurons. The role of Lhx6 in development of telencephalic and hypothalamic neurons differs in several important respects. Lhx6 expression is regulated by different transcription factors in the two regions. Preliminary gene expression analysis has identified a number of genes that are strong candidates for mediating these differences. In this proposal, we aim to identify the molecular mechanisms that guide the specification and survival of hypothalamic Lhx6 neurons. First, we will use a combination of genetic approaches to identify transcriptional regulatory networks that are required for initiation and maintenance of hypothalamic expression of Lhx6, and that control development of distinct subtypes of Lhx6-positive neurons. Next, we will determine whether tangential cell migration plays a critical role in the localization of sleep-promoting Lhx6-positive neurons, and identify the molecular mechanisms that control this process. Finally, we will identify molecular subtypes of sleep-activated Lhx6-positive hypothalamic neurons, and investigate how mutants that disrupt the development of these neurons result in altered regulation of the sleep/wake cycle. This will provide insight into molecular pathways that control the assembly of key components of hypothalamic neural circuitry, and may identify therapeutic targets for treatment of sleep disorders.