THE ONTOGENY OF 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-2 AND MINERALOCORTICOID RECEPTOR GENE-EXPRESSION REVEAL INTRICATE CONTROL OF GLUCOCORTICOID ACTION IN DEVELOPMENT

Glucocorticoids play important roles in development and 'fetal program ming'. Fetal exposure to excess glucocorticoids reduces birth weight a nd causes later hypertension. To investigate these processes further w e have determined the detailed ontogeny of 11 beta-hydroxysteroid dehy drogenase type2 (11 beta-HSD2, which potently inactivates glucocortico ids) and the mineralocorticoid receptor (MR) by in situ hybridisation from embryonic day 9.5 (E9.5, term = E19) until after birth in the mou se. Widespread abundant 11 beta-HSD2 mRNA expression from E9.5-E12.5 c hanges dramatically at approximate to E13 to a limited tissue-specific pattern (kidney, hindgut, testis, bile ducts, lung and a few brain re gions (later seen in cerebellum, thalamus, roof of midbrain, neuroepit helial regions in pons and near the subicular hippocampus)). Placenta (labyrinthine zone) and extra-embryonic membranes express abundant 11 beta-HSD2 mRNA until E15.5 but this ceases approximate to E16.5. It is unclear to what extent rodent term placental 11 beta-HSD activity is due to persisting 11 beta-HSD2 protein. Convincing MR mRNA expression is seen from E13.5 and includes pituitary, heart, muscle and meninges with expression later in gut, kidney, thymus, discrete areas of lung a nd several brain regions (including hippocampus, rhinencephalon and hy pothalamus). 11 beta-HSD2 and MR clearly co-localise approximate to E1 8.5 in kidney and colon and might do so in discrete areas of lung (E14 -15) and neuroepithelia near the subicular hippocampus. Probably elsew here MR are non-selective and 11 beta-HSD2 is involved in protecting g lucocorticoid receptors in fetal tissues. Comparison with previous enz ymology studies suggest the changing pattern of 11 beta-HSD2 mRNA is l ikely to be translated into enzyme activity and have significant paral lels in human development.