Regulation of gene expression in the ovine fetus.

Expression of genes encoding pro-opiomelanocortin (POMC), glucocorticoid receptors and 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) was studied in sheep fetuses during development. POMC mRNA was present in the anterior pituitary by day 60 of gestation (term approximately 145 days), and its relative amount did not change significantly until after days 125-130. The amount of POMC mRNA in the pituitary increased significantly at days 138-143, remained high at term and increased further in newborn lambs. In contrast, POMC mRNA could not be detected in the hypothalamus and adrenal glands of fetuses at all ages studied. These results suggest that the prepartum rise in plasma adrenocorticotrophin (ACTH) concentrations in sheep fetuses is due to increased expression of POMC gene in the pituitary. The number of glucocorticoid receptors, but not the amount of glucocorticoid receptor mRNA changed significantly with gestational age in the hypothalamus, anterior pituitary and adrenal glands of the fetus. Changes in glucocorticoid receptor content of fetal tissues may reflect alterations in translation of glucocorticoid receptor mRNA, subsequent modifications, or glucocorticoid receptor turnover or a combination of these factors. However, in newborn lambs, amounts of glucocorticoid receptor mRNA increased significantly in the hypothalamus and pituitary but decreased to undetectable amounts in the adrenal glands, indicating that tissue-specific factors may influence expression of glucocorticoid receptor gene in neonatal sheep. The interconversion of cortisol and cortisone requires 11 beta-HSD. Since cortisone is biologically inactive, 11 beta-HSD may regulate the activity of intracellular cortisol. We cloned and sequenced a cDNA encoding sheep 11 beta-HSD. By northern blot analysis, this cDNA detected a single 1.8 kb transcript in the fetal and adult sheep liver, lung, hypothalamus, anterior pituitary and placenta. This could not be detected in the adrenal glands and kidneys, but a smaller (1.5 kb) transcript was present in the fetal and adult kidneys. During fetal development, the relative amount of 11 beta-HSD mRNA did not change significantly in the kidney and lung, but increased in lungs from newborn lambs. In contrast, amounts of hepatic 11 beta-HSD mRNA not only increased significantly in the fetus at term but also displayed a further increase in the newborn. These results clearly indicate that expression of ovine 11 beta-HSD gene in the fetus and newborn is regulated in a tissue-specific and developmentally programmed manner.