The ultimate research goal of this lab is to decipher the gene regulatory network that directs the development of various types of neurons in the mouse arcuate nucleus of the hypothalamus (ARC). Despite the physiological significance of many ARC neurons, the developmental gene regulatory programs for ARC neurons remain poorly understood. This lab has been pioneering this emerging area of studies by successfully combining mouse genetics and genome-wide studies. Notably, a close developmental link has been discovered among different types of ARC neurons. These intertwined developmental pathways are likely crucial 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. Key preliminary results in this grant include: i) Single cell RNA-seq (scRNA-seq) analyses reveal eight TFs enriched in developing growth hormone-releasing hormone (GHRH)-neurons in the ARC, which control linear growth; Prox1, Gsx1, Egr1, Foxp2, Pbx3, St18, Dlx1 and Dlx2. Notably, Dlx1/2, Foxp2 and Gsx1 have been shown to be important for the development of GHRH-neurons, indicating that the scRNA-seq approach is highly useful to identify TFs acting on neuronal lineage development. ii) GHRH-specific inactivation of Prox1 leads to dwarfism and reduced Ghrh expression in mice. iii) Further, ChIP-seq data for Dlx1 provides various new insights into the mechanism by which Dlx1 controls GHRH-neuronal development. Together, these results led to the central hypothesis Dlx1/2 and Prox1 play vital roles in acquiring GHRH-neuronal fate over other related ARC neuronal lineages in part by coordinating the expression of downstream TFs. This hypothesis will be tested in the two specific aims using an ensemble of biochemical and cellular methods, mouse genetics and genome-wide approaches. Completion of this innovative study will radically improve the understanding of how common progenitors are guided to gain a specific ARC lineage identity over other related cell fates, providing a critical mechanism contributing to the balanced production of diverse ARC neuronal types during development.

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.