Development and function of hypothalamic Lhx6-positive neurons

项目摘要 下丘脑背外侧的GABA能神经元在调节 睡眠/觉醒周期，但对控制其发育的分子机制知之甚少。我们有 最近发现LIM同源结构域转录因子Lhx6是种群发育所必需的 促进睡眠的GABA能神经元在下丘脑的不确定带。Lhx6对于 大多数端脑中间神经元的发育和迁移，在下丘脑的Lhx6表达很多 不表达端脑Lhx6阳性中间神经元标记的更受限制的神经元亚群。这个 Lhx6在端脑和下丘脑神经元发育中的作用在几个重要方面有所不同。 Lhx6的表达受这两个区域不同转录因子的调控。初步基因表达 分析已经确定了一些基因，它们是调节这些差异的有力候选者。在这 建议，我们的目标是确定指导下丘脑的规范和存活的分子机制。 Lhx6神经元。首先，我们将使用基因方法的组合来识别转录调控 启动和维持下丘脑Lhx6表达所需的网络，以及控制 不同亚型Lhx6阳性神经元的发育。接下来，我们将确定切向单元格是否 迁移在促进睡眠的Lhx6阳性神经元的定位中起关键作用，并识别 控制这一过程的分子机制。最后，我们将确定睡眠激活的分子亚型 Lhx6阳性的下丘脑神经元，并研究破坏这些神经元发育的突变体 导致睡眠/清醒周期的调节发生改变。这将提供对控制分子途径的洞察 组装下丘脑神经回路的关键组件，并可能确定治疗靶点 睡眠障碍的治疗。

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.