Project Summary The research goal of Lee lab is to decipher the gene regulatory network that directs the embryonic development of various types of neurons in the mouse arcuate nucleus of the hypothalamus (ARC). Neurons in the ARC centrally regulate various homeostatic processes critical for survival and reproduction. Despite extensive studies on the physiological roles of ARC neurons, the gene regulatory programs for their development are poorly understood. Lee lab has been pioneering this challenging area of studies by successfully combining mouse genetics and genome-wide studies. In particular, Lee lab accomplished the first ChIP-Seq (for chromatin immunoprecipitation followed by sequencing) and scRNA-Seq (for single cell RNA-Seq) analyses with developing ARC. Interestingly, many ARC neurons share common developmental lineages. This is likely to be critical to ensure the balanced production of different ARC neurons during embryogenesis, enabling a highly coordinated regulation of various homeostatic processes in later postnatal life, such as integration of feeding, reproduction, and growth. By performing scRNA-Seq with E15 ARC, when ARC neurons actively develop, Le lab identified transcription factors that are highly likely to play critical roles in the development of ARC neurons. These include the TFs Dlx1/2 and Prox1, which are hypothesized to play vital roles in establishing GHRH- neuronal fate over other related ARC neuronal lineages. By testing this hypothesis using an ensemble of biochemical and cellular methods, mouse genetics and genome-wide approaches, Lee lab wishes to advance the understanding of how common progenitors are guided to take a specific linage over other related ARC neuronal fates, resulting in the balanced development of various ARC neuronal types during embryogenesis.

PROJECT NARRATIVE Understanding of the central regulation of growth and energy homeostasis is important to fight against dwarfism and various metabolic diseases. Despite great advances in physiological understanding of the hypothalamic neurons that control these processes, how they are formed during development is ill-defined, and this critical issue will be dissected in this proposal.