CONDITIONAL GENE TARGETING OF POMC IN THE HYPOTHALAMUS

Oregon Health And Science University, Portland OR

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Abstract

DESCRIPTION (Adapted from applicant's abstract): Neuropeptides produced in neurons are secreted and function in neuronal signaling and control of hormone secretion from the pituitary. Proopiomelanocortin (POMC) is the polypeptide precursor of several hormones including adrenocorticotropic hormone (ACTH), melanocyte-stimulating hormone (MSH), lipotropins (betaLPH and gammaLPH) and beta-endorphin. These neuropeptides play important roles as mediators of the stress response. Recent evidence suggests that POMC is also involved in central regulation of body weight. Further, the expression of POMC peptides and their receptors during neurogenesis indicates that POMC may play a role in the development of hypothalamic nuclei. We hope to identify a role for central nervous system (CNS) POMC in these neuroendocrine mediated events. To address possible POMC involvement in body weight and development, we propose to use gene targeting to delete POMC gene expression in mice. In addition, POMC expression will be stopped at discrete time points through the use of the Cre DNA recombinase enzyme and its target sequences, lox-P sites, flanking the POMC translated region. Removal of all POMC peptides at various time points will allow an examination of POMC function during development. Adult mutant mice will be analyzed for differences in feeding, body weight and development of their stress-axis. We will use a pituitary-targeted POMC transgene to rescue phenotypes due to the loss of pituitary POMC. The POMC-deficient mice and pituitary-POMC- rescued mice will help distinguish the roles of hypothalamic POMC and pituitary POMC in neuroendocrine regulation of development, stress, appetite, and body mass.