The role of Nkx genes in hypothalamic & NAc development

描述（由申请人提供）：拟定研究的目的是确定Nkx基因是否在下丘脑和丘脑核（NAc）中GABA能和NPY表达神经元的区域特化和发育中发挥作用。涉及进食失调的疾病包括：神经性厌食症、贪食症和普拉德-威利综合征。前脑中有两种机制调节食物摄入：自我平衡和享乐。摄食行为在下丘脑中受到稳态调节，而享乐或奖励系统则集中在NAc中。下丘脑和NAc中的神经元产生并响应食欲（食欲诱导）或食欲（饱腹感）信号，从而调节食欲。GABA和神经肽Y（NPY）是存在于下丘脑和NAc中的食欲信号。在前脑中，Nkx转录因子在GABA能神经元的背腹图案化和特化中具有主要作用。在整个发育过程中，Nkx2.1、Nkx2.2和Nkx2.9在与进食行为有关的大脑区域中表达。Nkx基因存在于祖细胞和神经元中，因此，可能是神经特性、分化和/或维持的特化所需的。首先，我将确定下丘脑和NAc中的哪些区域和神经元表达Nkx 2.1，Nkx 2.2和Nkx 2.9，并确定其他发育调控基因（例如，Dlx，SF 1，Shh）与Nkx基因共定位。我将分析这些基因在Nkx2.1突变小鼠中的表达。我还想使用在Nkx2.1和Nkx2.2启动子控制下表达Cre重组酶的小鼠对Nkx2.1+和Nkx 2.2+细胞进行命运图绘制，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在小鼠中分析Nkx2.1在下丘脑和NAc中的NPY+/GABA+神经元的背腹图案化、特化和分化中的功能。

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.