Genetic Analysis of the Role of Pro-opiomelanocortin Peptides in Mouse Adrenal Development

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The adrenal gland regulates essential physiological functions in the adult mammalian organism through producing gluco- and mineralocorticoids. Furthermore, through production of steroid hormones, the adrenal gland contributes to the normal maturation of fetal organ systems, including lung, liver, pancreas, brain, retina, and gastrointestinal tract. Several distinct signals have been implicated as critical for pre- and postnatal development and for maintenance of the mammalian adrenal gland. These include signals from the pituitary, such as pro-opiomelanocortin (POMC)-derived peptides, and signals derived from the cells of the adrenal itself, such as corticosterone. It is essential to know more specifically which factors are required for which aspects of adrenal development and maintenance. The principal investigator recently developed a strain of genetically engineered mutant mice lacking all POMC-derived peptides. These POMC null mice develop non-functional adrenal structures that completely disappear in the adult, thus affording a new opportunity to study the role of POMC peptides in adrenal development, maintenance, and function.In this proposal the investigators will systematically exploit the POMC knockout mouse to probe the molecular mechanisms regulating mammalian adrenal development and maintenance. The first objective is to determine whether POMC-derived peptides, either supplied from the mother or from the fetus, are essential for the prenatal development of the adrenal structure. To this end the investigators will analyze prenatal adrenal development in embryos when either the mother or the fetus or both lack POMC-derived peptides. The second objective is to determine whether POMC-derived peptides are essential for postnatal adrenal development and differentiation. The investigators will analyze postnatal adrenal development in pups lacking POMC-derived peptides, in POMC null mutant pups, which are pharmacologically reconstituted with individual or combinations of POMC peptides, and by postnatal transplantation of adrenals from wildtype and mutant donors to recipients having or lacking POMC peptides. The third objective is to assess the role of POMC-derived peptides in maintaining adult adrenal structure and function. The investigators will assess the maintenance of adrenal glands in mice lacking POMC peptides by transplanting normal adrenal tissue into POMC null mutant mice and reconstituting these mice with individual POMC peptides, and by subtraction of individual POMC peptides in POMC null mutants which have developed adrenals through postnatal reconstitution with POMC peptides. This genetic dissection of the role of POMC peptides in pre-and postnatal adrenal development and maintenance will provide a detailed and necessary framework for the study of the molecular mechanisms generating and maintaining this important organ.