Transcription factors governing the development of GHRH-neurons

项目摘要 Lee实验室的研究目标是破译指导胚胎发育的基因调控网络 对小鼠下丘脑弓状核（ARC）内不同类型神经元的形态结构进行了研究。ARC中的神经元 中枢调节各种对生存和繁殖至关重要的稳态过程。尽管有大量的研究 关于ARC神经元的生理作用，其发育的基因调控程序很少 明白Lee实验室一直在开拓这一具有挑战性的研究领域， 遗传学和全基因组研究。特别是，Lee实验室完成了第一个ChIP-Seq（用于染色质 免疫沉淀，然后测序）和scRNA-Seq（用于单细胞RNA-Seq）分析， 发展ARC。有趣的是，许多ARC神经元具有共同的发育谱系。这很可能是 这对于确保胚胎发生期间不同ARC神经元的平衡产生至关重要， 协调调节出生后后期生活中的各种稳态过程，如喂养的整合， 繁殖和生长。通过用E15 ARC进行scRNA-Seq，当ARC神经元活跃发育时， 实验室鉴定了在ARC神经元发育中极有可能发挥关键作用的转录因子。 这些包括TF Dlx 1/2和Prox 1，它们被假设在建立GHRH中发挥重要作用。 神经元的命运超过其他相关的ARC神经元谱系。通过使用以下集合来测试这一假设， 生物化学和细胞方法，小鼠遗传学和全基因组方法，李实验室希望推进 了解共同的祖先是如何被引导采取一个特定的血统，而不是其他相关的ARC 神经元的命运，导致各种ARC神经元类型在胚胎发育过程中的平衡发展。

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.