Fetal glucocorticoid synthesis is required for development of fetal adrenal medulla and hypothalamus feedback suppression.

During pregnancy, fetal glucocorticoid is derived from both maternal supply and fetal secretion. We have created mice with a disruption of the Cyp11a1 gene resulting in loss of fetal steroid secretion but preserving the maternal supply. Cyp11a1null embryos have appreciable although lower amounts of circulating corticosterone, the major mouse glucocorticoid, suggesting that transplacental corticosterone is a major source of corticosterone in fetal circulation. These embryos thus provide a means to examine the effect of fetal glucocorticoids. The adrenal in Cyp11a1 null embryos was disorganized with abnormal mitochondria and oil accumulation. The adrenal medullary cells did not express phenylethanolamine N-methyltransferase and synthesized no epinephrine. Cyp11a1 null embryos had decreased diencephalon Hsd11b1, increased diencephalon Crh, and increased pituitary Pomc expression, leading to higher adrenocorticotropin level in the plasma. These data indicate blunted feedback suppression despite reasonable amounts of circulating corticosterone. Thus, the corticosterone synthesized in situ by the fetus is required for negative feedback suppression of the hypothalamus-pituitary-adrenal axis and for catecholamine synthesis in adrenal medulla.

Regulation of steroid production: analysis of Cyp11a1 promoter.

CYP11A1 is a key enzyme in steroid synthesis abundantly expressed in the adrenal, testis, ovary, and placenta. This article reviews recent studies on cis-regulatory elements and trans-regulators of the CYP11A1 promoter, with special focus on their tissue-specific regulation. Trans-regulators include tissue-specific factors such as SF-1, DAX-1, TReP-132, LBP, and GATA that regulate tissue-specific expression of CYP11A1. These tissue-specific factors interact with factors commonly present in most cells like AP-1, Sp1, and AP-2 to bring CYP11A1 transcription to full potential. These transcription factors stimulate CYP11A1 transcriptional activity through interaction with their specific cis-elements or through protein-protein interaction. The cis-element on the Cyp11a1 promoter was further characterized in vitro and in vivo. Mutation of the proximal SF-1-binding site results in down regulation of CYP11A1 in the adrenal and testis but not in the ovary and placenta, leading to attenuated corticosterone circadian rhythms and blunted stress response.