Investigating molecular mechanisms and function of tanycyte-derived neurogenesis in the postnatal hypothalamus

研究出生后下丘脑单胞衍生神经发生的分子机制和功能

• 批准号: 10676116
• 负责人: Leighton Hosea Duncan
• 金额: $ 2.28万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10676116
• 关键词: Action Potentials; Address; Adolescent; Adult; Agonist; Area; Astrocytes; Body Composition; Body Weight; Cell Count; Cells; Competence; Cues; Development; Down-Regulation; Energy Metabolism; Family; Fibrinogen; Fire - disasters; Gene Expression; Gene Expression Profile; Genes; Goals; High Fat Diet; Homeostasis; Hormonal; Hypothalamic structure; Immunohistochemistry; Injections; Intraperitoneal Injections; Label; Leptin; Maps; Measures; Metabolic; Metabolic Diseases; Metabolism; Molecular; Morphology; Muller' s cell; Mus; Neuroglia; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Notch Signaling Pathway; Nuclear; Obesity; Pathway interactions; Physiological; Play; Proliferating; Radial; Regulation; Retina; Role; Signal Pathway; Therapeutic; Tissue-Specific Gene Expression; WNT Signaling Pathway; Work; antagonist; combinatorial; design; dietary; differential expression; experimental study; gamma secretase; gene regulatory network; insight; leptin receptor; loss of function; male; nerve stem cell; neural circuit; neurogenesis; neuronal survival; notch protein; obesogenic; postnatal; single-cell RNA sequencing; transcription factor; virtual; young adult

PROJECT SUMMARY In recent years, evidence now shows that tanycytes possess the ability to generate neurons in the postnatal hypothalamus. Tanycytes are radial glial cells that closely resemble neural progenitors in both morphology and gene expression profiles. While dietary and hormonal cues can regulate tanycyte-derived neurogenesis, the overall levels of tanycyte proliferation and tanycyte-derived neurogenesis are low and virtually undetectable in adult mice. The molecular mechanisms controlling neurogenic competence in tanycytes, and the precise physiological function of tanycyte-derived neurons remains poorly defined. Identifying molecular mechanisms that stimulate tanycyte-derived neurogenesis, to promote differentiation of tanycyte-derived neurons that modulate body weight and metabolism, is a new potential therapeutic for treating obesity and metabolic disorders such as type II diabetes. Recently, studies from the Blackshaw lab have identified the Nuclear Factor One (Nfi) family transcription factors (TFs), Nfia/b/x, as playing a critical role in regulating neurogenic competence in hypothalamic tanycytes. Under normal dietary conditions in male mice, Nfia/b/x-deficient tanycytes show enhanced proliferation and neurogenesis. Single-cell RNA-sequencing analysis of Nfia/b/x-deficient tanycytes and tanycyte-derived cells indicates that a substantial fraction of all tanycyte-derived neurons are GABAergic subtypes. A subset of these GABAergic neurons expresses the Leptin receptor (Lepr) and responds to leptin. The Blackshaw lab has also shown that tanycyte-derived neurons survive, integrate into hypothalamic circuits, and fire spontaneous action potentials. By analyzing genes differentially expressed between control and Nfia/b/x-deficient tanycytes, we have shown that Shh and Wnt signaling is upregulated in tanycytes following loss of Nfia/b/x. We also observed the downregulation of the Notch pathway in Nfia/b/x-deficient tanycytes. During development, Shh and Wnt pathways promotes neurogenesis in the hypothalamus. While Notch signaling pathway promote quiescence in retinal Müller glia and cortical astrocytes. Given these findings, I hypothesize that neurogenic competence in tanycytes is actively suppressed in the postnatal hypothalamus after neurogenesis and, hypothesize that tanycyte-derived neurons regulate body weight homeostasis and metabolism. To address these hypotheses, I propose the following two Aims: AIM 1: To investigate extrinsic regulators that positively or negatively control tanycyte-derived neurogenesis in the juvenile and young adult hypothalamus. This work will identify molecular mechanisms and gene regulatory networks that positively or negatively regulate tanycyte-derived neurogenesis in the postnatal hypothalamus. AIM 2: To determine the role of tanycyte-derived neurons on bodyweight homeostasis and metabolism. These studies will provide key insights into the physiological function of tanycyte-derived neurons in controlling body weight homeostasis and metabolism.

项目摘要 近年来，现在的证据表明，坦西氏菌具有在 产后下丘脑。 tanycytes是径向神经胶质细胞，在两者中都非常类似于神经祖细胞 形态和基因表达谱。虽然饮食和马线提示可以调节tanycyte的衍生 神经发生，丹氏胞菌增殖的总体水平和tanycyte衍生的神经发生较低，并且 成年小鼠几乎无法检测。控制神经源能力的分子机制 tanycytes以及tanycyte衍生的神经元的精确生理功能仍然很差。 鉴定刺激tanycyte衍生的神经发生的分子机制，以促进分化 调节体重和新陈代谢的tanycyte衍生的神经元是治疗的新潜在疗法 肥胖和代谢性疾病，例如II型糖尿病。 最近，来自Blackshaw实验室的研究确定了核因子一（NFI）家族转录 因素（TFS），NFIA/B/X，是控制下丘脑神经源能力的关键作用 tanycytes。在雄性小鼠的正常饮食条件下，NFIA/B/X缺陷tanycytes显示出增强的 增殖和神经发生。 NFIA/B/X缺陷tanycytes和 tanycyte衍生的细胞表明，所有tanycyte衍生的神经元的大部分是Gabaergic 亚型。这些GABA能神经元的子集表达瘦素受体（LEPR）并对瘦素反应。 黑肖实验室还表明，丹尼西特衍生的神经元可以存活，整合到下丘脑电路中， 和火灾赞助的行动潜力。通过分析的基因在对照和对照之间的不同表达 nfia/b/x缺乏的tanycytes，我们已经证明了shh和wnt信号在tanycytes中上调 NFIA/B/X的损失。我们还观察到NFIA/B/X缺陷型tanycytes中Notch途径的下调。 在开发过程中，SHH和WNT途径促进下丘脑的神经发生。当缺口 信号通路可促进视网膜müller神经胶质和皮质星形胶质细胞的静止。有了这些发现，我 假设tanycytes中的神经源能力在产后被积极抑制 神经发生后的下丘脑，并假设tanycyte衍生的神经元调节身体 体重稳态和代谢。为了解决这些假设，我提出了以下两个目标： 目的1：调查积极或负面控制tanycyte衍生的外部调节器 少年和成年下丘脑的神经发生。这项工作将确定分子机制 和基因调节网络，这些网络在正调节tanycyte衍生的神经发生的基因调节网络中 产后下丘脑。 目的2：确定坦伊养生神经元对体重稳态和代谢的作用。 这些研究将为控制tanycyte衍生的神经元的身体功能提供关键的见解 体重体内稳态和代谢。