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细胞发育的基因调控网络。 小鼠下丘脑弓状核（ARC）中的各种类型的神经元。尽管生理上 许多 ARC 神经元的重要性，但 ARC 神经元的发育基因调控程序仍然很差 明白了。该实验室通过成功地将小鼠与 遗传学和全基因组研究。值得注意的是，不同群体之间发现了密切的发展联系。 ARC 神经元的类型。这些相互交织的发展途径可能对于确保平衡至关重要 在胚胎发生过程中产生不同的 ARC 神经元，从而能够高度协调地调节各种 产后生活中的稳态过程，例如进食、繁殖和生长的整合。 本次资助的主要初步结果包括： i) 单细胞 RNA-seq (scRNA-seq) 分析揭示了 8 个 TF ARC 中富含发育中的生长激素释放激素 (GHRH) 神经元，控制线性 生长; Prox1、Gsx1、Egr1、Foxp2、Pbx3、St18、Dlx1 和 Dlx2。值得注意的是，Dlx1/2、Foxp2 和 Gsx1 已被 已被证明对 GHRH 神经元的发育很重要，表明 scRNA-seq 方法高度有效 对于识别作用于神经元谱系发育的 TF 很有用。 ii) Prox1 的 GHRH 特异性失活导致 侏儒症和小鼠 Ghrh 表达减少。 iii) 此外，Dlx1 的 ChIP-seq 数据提供了各种新的见解 深入了解 Dlx1 控制 GHRH 神经元发育的机制。这些结果共同导致 中心假设 Dlx1/2 和 Prox1 在获得 GHRH 神经元命运方面比其他相关的神经元命运起着至关重要的作用 ARC 神经元谱系部分通过协调下游 TF 的表达来实现。这个假设将是 使用生化和细胞方法、小鼠遗传学和 全基因组方法。这项创新研究的完成将从根本上提高对如何 共同祖细胞被引导获得相对于其他相关细胞命运的特定 ARC 谱系身份，从而提​​供 发育过程中促进不同 ARC 神经元类型平衡产生的关键机制。