Developmental Links between the Fetal and Adult Zones of the Adrenal Cortex Revealed by Lineage Tracing

Abstract

The nuclear receptor Ad4BP/SF-1 is essential for development of the adrenal cortex and the gonads, which derive from a common adrenogonadal primordium. The adrenal cortex subsequently 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 adrenal and gonadal primordia and the fetal and adult adrenal cortices remain incompletely understood. We previously identified a fetal adrenal-specific enhancer (FAdE) in the Ad4BP/SF-1 locus that directs transgene expression to the fetal adrenal cortex and demonstrated that this enhancer is autoregulated by Ad4BP/SF-1. We now combine 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 eventuates in cells of the adult cortex disappeared by embryonic day 14.5. Thus, these studies demonstrate a direct link between the fetal and adult cortices involving a transition that must occur before a specific stage of development.

Transition from organogenesis to stem cell maintenance in the mouse adrenal cortex

“…22 Lineage analysis with tamoxifen-inducible reporters showed that labeling of Shh-expressing cells in the outer cortex at E14.5 gave rise to postnatal clones of labeled cells extending from the periphery almost to the medulla by 28 d after reporter induction. Crucially, however, while cell labeling was initiated at E14.5, shortly after the adult adrenocortical lineage becomes established, 15 this is likely to be well before adult adrenocortical stem cells are activated. Thus, it is possible that clonal lineages, spanning most of the cortex, include cells produced both before and after stem cells are activated.…”

“…Elegant transgenic lineage analyses of mouse adrenocortical organogenesis and maintenance have shown (1) that distinct groups of fetal adrenocortical cells with a common origin form the X zone and definitive adult adrenal cortex 14,15 and (2) that progenitor cells labeled at E14.5 can produce clones of cells that span the cortex and produce all the steroidogenic cell types of the adrenal cortex. 22 Our present results bridge these two observations and show that perinatal adrenal cortical growth occurs by edge-biased growth.…”

“…22 Our present results bridge these two observations and show that perinatal adrenal cortical growth occurs by edge-biased growth. This presumably represents the expansion of the population of cells in the fetal adrenal, forming a distinct adult lineage from around E14.5 15 that develops into the adult adrenal cortex (rather than the X zone). This period of edgebiased growth coincides with the first signs of radial stripes in mosaic 21OH/LacZ, implying that the initial adrenocortical stripes are formed by edge-biased growth and so resembles stripe Figure 6.…”

“…In adults, radial stripes span the whole adrenal cortex, from the capsule to the medulla, so it is necessary to explain how developing stripes extend into older cortical regions displaying randomly orientated mosaic patterns and eventually adrenal glands before zonation occurs. 10,15 This intermingling is gradually resolved after birth.…”

“…14 Lineage tracing has also shown that the adult adrenal cortex is derived directly from fetal adrenocortical cells, forming a distinct adult lineage from around E14.5. 15 The diffuse pale blue β-gal staining, observed in postnatal 21OH/LacZ adrenals at the cortical-medullary boundary in females at P7 and in males at P10 may mark the condensing X zone before it can be identified morphologically. Figure 5.…”