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

肾上腺通过产生糖皮质激素和矿皮质激素来调节成年哺乳动物机体的基本生理功能。此外，通过产生类固醇激素，肾上腺有助于胎儿器官系统的正常成熟，包括肺、肝、胰腺、脑、视网膜和胃肠道。几个不同的信号被认为是哺乳动物肾上腺产前和产后发育和维持的关键信号。这些信号包括来自垂体的信号，如POMC衍生的肽，以及来自肾上腺本身细胞的信号，如皮质酮。有必要更具体地了解肾上腺发育和维持的哪些方面需要哪些因素。首席研究员最近开发了一种缺乏所有pomc衍生肽的基因工程突变小鼠。这些POMC缺失的小鼠产生了在成年小鼠中完全消失的无功能肾上腺结构，从而为研究POMC肽在肾上腺发育、维持和功能中的作用提供了新的机会。在这个提议中，研究者将系统地利用POMC敲除小鼠来探索调节哺乳动物肾上腺发育和维持的分子机制。第一个目的是确定pomc衍生肽，无论是来自母亲还是来自胎儿，是否对产前肾上腺结构的发育至关重要。为此，研究人员将分析母亲或胎儿或双方都缺乏pomc衍生肽时胚胎的产前肾上腺发育情况。第二个目的是确定pomc衍生肽是否对出生后肾上腺发育和分化至关重要。研究人员将分析缺乏POMC衍生肽的幼崽、POMC零突变幼崽（用POMC肽的单个或组合进行药理学重组）以及将野生型和突变型供体的肾上腺移植给具有或缺乏POMC肽的受体的出生后肾上腺发育情况。第三个目的是评估pomc衍生肽在维持成人肾上腺结构和功能中的作用。研究人员将通过将正常肾上腺组织移植到POMC缺失突变小鼠中，并用单个POMC肽重建这些小鼠，以及通过POMC缺失突变小鼠中通过出生后用POMC肽重建产生肾上腺的POMC缺失突变体中减去单个POMC肽，来评估缺乏POMC肽的小鼠肾上腺的维持情况。对POMC肽在产前和产后肾上腺发育和维持中的作用的遗传解剖将为研究这一重要器官的产生和维持的分子机制提供详细和必要的框架。

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.