The role of Nkx genes in hypothalamic & NAc development

Nkx 基因在下丘脑中的作用

• 批准号: 7105622
• 负责人: CINDY L YEE
• 金额: $ 4.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7105622
• 关键词: appetite; brain mapping; cell differentiation; developmental genetics; eating; gamma aminobutyrate; gene induction /repression; hypothalamus; laboratory mouse; neurogenesis; neurogenetics; neuropeptide Y; nucleus accumbens; postdoctoral investigator

DESCRIPTION (provided by applicant): The goal of the proposed research is to determine whether Nkx genes play a role in regional specification and development of GABAergic and NPY expressing neurons in the hypothalamus and nucleus accumbens (NAc). Disorders that involve dysregulation of feeding include: anorexia nervosa, bulimia and Prader-Willi syndrome. Food intake is regulated by two mechanisms in the forebrain: homeostatic and hedonic. Feeding behavior is homeostatically regulated in the hypothalamus, whereas hedonic or reward systems are centered in the NAc. Neurons in the hypothalamus and NAc generate and respond to orexigenic (appetite inducing) or anorexigenic (satiety) signals, thereby regulating appetite. GABA and Neuropeptide Y (NPY) are orexigenic signals present in the hypothalamus and NAc. In the forebrain, Nkx transcription factors have major roles in dorsoventral patterning and specification of GABAergic neurons. Throughout development, Nkx2.1, Nkx2.2 and Nkx2.9 are expressed in brain regions implicated in feeding behavior. Nkx genes are present in both progenitors and in neurons, and thus, may be required for specification of neural identity, differentiation and/or maintenance. First, I will determine which regions and neurons in the hypothalamus and NAc express Nkx 2.1, Nkx 2.2 and Nkx2.9 and identify other developmentally regulated genes (e.g., Dlx, SF1, Shh) that colocate with Nkx genes. I will analyze the expression of these genes in Nkx2.1 mutant mice. I would also like to fate map Nkx2.1+ and Nkx 2.2+ cells using mice expressing Cre recombinase under the control of the Nkx2.1 and Nkx2.2 promoters, and determine the neuronal contribution of Nkx progenitors in the adult hypothalamus and NAc. I will analyze Nkx2.1 function in dorsoventral patterning, specification and differentiation of NPY+/GABA+ neurons in the hypothalamus and NAc using cre recombinase-mediated gene inactivation technology in mice.

描述（由申请人提供）：拟研究的目的是确定Nkx基因是否在下丘脑和伏隔核（NAc）表达GABAergic和NPY神经元的区域规范和发育中发挥作用。涉及进食失调的疾病包括：神经性厌食症、贪食症和普瑞德-威利综合征。食物摄入是由前脑中的两种机制调节的：内稳态机制和享乐机制。进食行为是由下丘脑调节的，而享乐或奖励系统则集中在中脑皮层。下丘脑和NAc中的神经元产生并响应致氧（食欲诱导）或厌氧（饱腹感）信号，从而调节食欲。GABA和神经肽Y （NPY）是下丘脑和NAc中存在的促氧信号。在前脑中，Nkx转录因子在gaba能神经元的背腹侧模式和规范中起主要作用。在整个发育过程中，Nkx2.1、Nkx2.2和Nkx2.9在与摄食行为有关的大脑区域表达。Nkx基因既存在于祖细胞中，也存在于神经元中，因此，可能需要它来规范神经的身份、分化和/或维持。首先，我将确定下丘脑和NAc中哪些区域和神经元表达Nkx 2.1、Nkx 2.2和Nkx2.9，并确定与Nkx基因搭配的其他发育调节基因（如Dlx、SF1、Shh）。我将分析这些基因在Nkx2.1突变小鼠中的表达。我还想利用表达Cre重组酶的小鼠在Nkx2.1和Nkx2.2启动子的控制下绘制Nkx2.1+和Nkx2.2 +细胞的命运图谱，并确定Nkx祖细胞在成人下丘脑和NAc中的神经元贡献。我将使用cre重组酶介导的基因失活技术分析Nkx2.1在小鼠下丘脑和NAc中NPY+/GABA+神经元的背腹侧模式、规范和分化中的功能。