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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要近年来，有证据表明单细胞具有在大脑中产生神经元的能力。出生后下丘脑的单细胞是放射状胶质细胞，与两者的神经祖细胞非常相似。而饮食和激素线索可以调节单细胞衍生的形态和基因表达谱。神经发生，单胞增殖和单胞衍生的神经发生的总体水平较低并且在成年小鼠中几乎检测不到控制神经源能力的分子机制。 tanycyte，以及 tanycyte 衍生神经元的精确生理功能仍然不清楚。识别刺激单胞衍生神经发生的分子机制，以促进分化调节体重和新陈代谢的单胞衍生神经元是一种新的潜在治疗方法肥胖和代谢紊乱，如 II 型糖尿病。最近，Blackshaw 实验室的研究发现了核因子一 (Nfi) 家族转录因素（TF），Nfia/b/x，在调节下丘脑神经源性能力中发挥着关键作用在雄性小鼠的正常饮食条件下，Nfia/b/x 缺陷的单胞细胞表现出增强。 Nfia/b/x 缺陷型单细胞的增殖和神经发生。长丝细胞衍生的细胞表明所有长丝细胞衍生的神经元中有很大一部分是 GABA 能的这些 GABA 能神经元的一个子集表达瘦素受体 (Lepr) 并对瘦素做出反应。 Blackshaw 实验室还表明，单胞衍生的神经元能够存活并整合到下丘脑回路中，通过分析对照和火自发动作电位之间差异表达的基因。 Nfia/b/x 缺陷的 tanycytes，我们发现 Shh 和 Wnt 信号在 tanycytes 中上调我们还观察到 Nfia/b/x 缺陷的单细胞中 Notch 通路的下调。在发育过程中，Shh 和 Wnt 通路促进下丘脑的神经发生。鉴于这些发现，我认为信号通路促进视网膜穆勒神经胶质细胞和皮质星形胶质细胞的静止。研究发现，单胞细胞的神经源能力在出生后受到积极抑制神经发生后的下丘脑，单细胞衍生的神经元调节身体为了解决这些假设，我提出以下两个目标：目标 1：研究正向或负向控制单胞衍生的外在调节因子这项工作将确定青少年和年轻成人下丘脑的神经发生的分子机制。以及正向或负向调节单胞衍生神经发生的基因调控网络产后下丘脑。目标 2：确定单细胞衍生神经元对体重稳态和代谢的作用。这些研究将为了解单细胞衍生神经元在控制中的生理功能提供重要见解。体重稳态和新陈代谢。