Development and function of hypothalamic Lhx6-positive neurons

下丘脑 Lhx6 阳性神经元的发育和功能

• 批准号: 10372173
• 负责人: Seth Blackshaw
• 金额: $ 40.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10372173
• 关键词: ATAC-seq; Anterior; Defect; Development; Elements; Gene Expression Profiling; Genes; Genetic study; Homeostasis; Hypothalamic structure; Interneurons; Maintenance; Mediating; Molecular; Neurons; Pathway interactions; Play; Population; Posterior Hypothalamus; Process; Regulatory Element; Role; Signal Transduction; Sleep; Sleep Disorders; Sleep Wake Cycle; Testing; Work; cell motility; experimental study; genetic analysis; genetic approach; homeodomain; inhibitory neuron; insight; migration; molecular subtypes; mutant; neural circuit; neuron development; new therapeutic target; pressure; selective expression; sleep regulation; therapeutic target; transcription factor; transcription regulatory network; zona incerta

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.

项目摘要 背外侧下丘脑的GABA能神经元在调节中起着至关重要的作用 睡眠/唤醒周期，但对控制其发育的分子机制知之甚少。我们有 最近发现，LIM同源域转录因子LHX6对于发展人群是必需的 下丘脑中Zona Incerta中促进睡眠的GABA能神经元的。 LHX6对于 下丘脑LHX6中大多数脑脑膜中间神经元的开发和迁移 不表达端脑LHX6阳性中间神经元标记的神经元的受限制子集。这 LHX6在端脑和下丘脑神经元发展中的作用在几个重要方面有所不同。 LHX6表达受两个区域中不同转录因子的调节。初步基因表达 分析已经确定了许多基因，这些基因是介导这些差异的强大候选者。在这个 提案，我们旨在确定指导下丘脑规范和存活的分子机制 LHX6神经元。首先，我们将使用遗传方法的组合来识别转录调节 启动和维持下丘脑表达LHX6所需的网络，该控制 LHX6阳性神经元的不同亚型的发展。接下来，我们将确定切向单元是否 迁移在促进睡眠LHX6阳性神经元的定位中起着至关重要的作用，并确定 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阳性下丘脑神经元，并研究如何破坏这些神经元发展的突变体 导致睡眠/唤醒周期的调节改变。这将提供对控制的分子途径的见解 下丘脑神经回路的关键组成部分的组装，并可能确定 治疗睡眠障碍。