The role of Nkx genes in hypothalamic & NAc development

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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.