Development and function of hypothalamic Lhx6-positive neurons

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.