The role of Nkx genes in hypothalamic & NAc development

描述(申请人提供)：拟议研究的目标是确定Nkx基因是否在下丘脑和伏隔核(NAC)GABA能和NPY表达神经元的区域指定和发育中发挥作用。涉及摄食失调的疾病包括：神经性厌食症、暴食症和普雷德-威利综合征。食物摄入量由前脑中的两种机制调节：内稳态和享乐性。摄食行为在下丘脑中以稳态方式调节，而享乐性或奖赏系统则集中在NAC。下丘脑和NAC中的神经元产生并对食欲(食欲诱导)或厌食(饱腹感)信号做出反应，从而调节食欲。GABA和神经肽Y(NPY)是存在于下丘脑和NAc的食欲信号。在前脑中，Nkx转录因子在背腹模式和GABA能神经元的规范中起着重要作用。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都有表达。NKX基因既存在于神经前体细胞中，也存在于神经元中，因此可能是神经识别、分化和/或维持所必需的。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，并确定其他与Nkx基因共存的发育调控基因(如DLx、SF1、Shh)。我将分析这些基因在Nkx2.1突变小鼠中的表达。我还想在Nkx2.1和Nkx2.2启动子的控制下，用表达Cre重组酶的小鼠来定位Nkx2.1+和Nkx2.2+细胞，并确定Nkx前体细胞在成年下丘脑和NAC中的神经元贡献。我将利用cre重组酶介导的基因失活技术，分析Nkx2.1在小鼠背腹侧模式、下丘脑和NAC中NPY+/GABA+神经元的指定和分化中的作用。

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.