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Transcription Factors Governing the Development of GHRH-neurons

控制 GHRH 神经元发育的转录因子

基本信息

批准号：
10676744
负责人：
JAE W LEE
金额：
$ 54.79万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10676744
关键词：
Area Binding Biochemical Cells ChIP-seq Data Data Set Development Developmental Gene Dwarfism Embryo Embryonic Development Ensure Exclusion FOXP2 gene Genes Genome Mappings Goals Grant Growth Growth and Development function Homeostasis Hypothalamic structure Immunohistochemistry Impairment In Situ Hybridization Individual Knockout Mice Life Link Metabolic Diseases Methods Molecular Mus Mutant Strains Mice Neurons Pathway interactions Pattern Physiological Play Process Production Regulation Regulator Genes Regulatory Pathway Reporting Reproduction Research Role Somatotropin-Releasing Hormone Structure of nucleus infundibularis hypothalami Testing Time Work biomarker panel cell type chromatin immunoprecipitation conditional knockout course development energy balance experimental study feeding fighting gene regulatory network genome-wide genome-wide analysis improved in vivo innovation insight mouse genetics mouse genome neuron development novel postnatal progenitor programs single-cell RNA sequencing transcription factor transcriptome

项目摘要

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.

本实验室的最终研究目标是破译指导发育的基因调控网络