The fetal and adult adrenal cortex

The orphan nuclear receptor AD4BP/SF-1 (adrenal-4-binding protein/steroidogenic factor-1 (NR5A1)) is essential for the proper development and function of reproductive and steroidogenic tissues. Although the expression of Ad4BP/Sf-1 is specific for those tissues, the mechanisms underlying this tissue-specific expression remain unknown. Our transgenic studies have identified the tissue-specific enhancers for the fetal adrenal cortex, ventromedial hypothalamus, and pituitary in Ad4BP/Sf-1 gene. The adrenal cortex forms morphologically distinct compartments, the inner (fetal) and outer (definitive or adult) zones. Despite considerable effort, the mechanisms that mediate the differential development of the fetal and adult adrenal cortex remain incompletely understood. It remained controversial whether a true fetal type adrenal cortex is present in mice, and this argument was complicated by the postnatal development of the so-called X-zone. Using transgenic mice with lacZ driven by the fetal adrenal enhancer (FAdE), we clearly identified a fetal adrenal cortex in mice, and the X-zone is the fetal adrenal cells accumulated at the juxtamedullary region after birth. We combined the FAdE with the Cre/loxP system to trace cell lineages in which the FAdE was active at some stage in development. These lineage tracing studies establish definitively that the adult cortex derives from precursor cells in the fetal cortex in which the FAdE was activated before the organization into two distinct zones. The potential of these fetal adrenocortical cells to enter the pathway that eventuate in cells of the adult cortex disappeared by E14.5. Thus, these studies demonstrate a direct link between the fetal and adult cortex involving a transition that must occur before a specific stage of development.