Transcription factors governing the development of GHRH-neurons

控制 GHRH 神经元发育的转录因子

• 批准号: 10458766
• 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
• 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/10458766
• 关键词: Area; Binding; Biochemical; Cells; ChIP-seq; Data; Data Set; Development; Developmental Gene; Dwarfism; Embryo; Embryonic Development; Ensure; FOXP2 gene; Genes; Goals; Grant; Growth; Growth and Development function; Homeostasis; Hypothalamic structure; Immunohistochemistry; Impairment; In Situ Hybridization; Individual; Knockout Mice; Life; Link; Maps; 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; fight against; 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

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.

该实验室的最终研究目标是破译指导发展的基因调节网络 下丘脑（ARC）的小鼠弧形核中的各种类型的神经元。尽管有生理 许多电弧神经元的意义，弧神经元的发育基因调节程序仍然很差 理解。该实验室一直在成功地结合小鼠来开创这一新兴研究领域 遗传学和全基因组研究。值得注意的是，在不同的不同 弧神经元的类型。这些交织在一起的发展途径对于确保平衡很可能 在胚胎发生过程中产生不同的弧神经元，从而实现高度协调的调节 后来产后生活中的稳态过程，例如喂养，繁殖和生长的整合。 该赠款的关键初步结果包括：i）单细胞RNA-Seq（SCRNA-SEQ）分析显示八个TFS 富含生长激素释放激素（GHRH）的神经元在ARC中控制线性的神经元 生长; PROX1，GSX1，EGR1，FOXP2，PBX3，ST18，DLX1和DLX2。值得注意的是，DLX1/2，FOXP2和GSX1已经 证明对GHRH-神经元的发展很重要，表明SCRNA-SEQ方法很高 对于识别作用于神经元谱系发育的TFs有用。 ii）Prox1的GHRH特异性灭活导致 矮小和小鼠的GHRH表达降低。 iii）此外，DLX1的CHIP-SEQ数据提供了各种新见解 DLX1控制GHRH神经元发育的机制。这些结果一起导致了 中央假设DLX1/2和Prox1在获得其他相关相关的GHRH-神经元命运方面起着至关重要的作用 弧神经元谱系部分通过协调下游TF的表达。这个假设将是 使用生化和细胞方法集合，小鼠遗传学和 全基因组的方法。这项创新研究的完成将从根本上提高对如何的理解 指导共同的祖细胞以比其他相关细胞命运获得特定的弧谱系身份，从而提​​供 在发育过程中，有助于平衡产生各种弧神经元类型的关键机制。