Endocrine Abstracts

The adrenal cortex is a dynamic organ that undergoes self-renewal. In the mouse it is divided into two concentric layers, the outer zona glomerulosa (ZG) and the inner zona fasciculata (ZF), that secrete aldosterone and corticosterone, respectively. Capsular and subcapsular stem/progenitor cells differentiate and migrate in a centripetal fashion to repopulate the gland until they reach the juxtamedullary region where they undergo senescence and apoptosis. Cell fate mapping studies have shown that the maintenance of the cortex relies on a pool of two interconnected cell populations, subcapsular undifferentiated cells secreting the morphogen Sonic Hedgehog (Shh) and capsular Gli1⁺ cells, which can transduce the Shh signal. Our lab has shown that Delta like non-canonical Notch ligand 1 (Dlk1) is expressed in partially undifferentiated cells of the subcapsular region in rat and human adrenals, whilst it is mostly expressed in capsular cells in mice. Our recent lineage tracing analyses used a tamoxifen inducible Dlk1^CreERT2 mouse model carrying the R26tdTom reporter. Injection of pregnant dames at embryonic day (e) 12.5 and analysis of tdTomato expression at postnatal day (p) 10 and p38 showed that 35% (p10) and 24% (p38) of Steroidogenic Factor 1(Sf1)+ cortical cells were tdTomato+. On the other hand, postnatal tamoxifen injections showed tdTomato+/Sf1+ cells only in 1-2% in cortical cells. This data indicates that capsular Dlk1 marks a population of adrenocortical progenitor cells, that are mostly active during embryonic development and near-dormant postnatally. However, postnatal Dlk1+ cells could be reactivated and contribute to the regeneration of the ZF after dexamethasone-induced atrophy. Mice were administered tamoxifen followed by 7 days of dexamethasone which resulted in ZF atrophy. Two weeks after removal of dexamethasone, regrowth of the ZF occurred and tdTomato+ cells were visible in the cortex suggesting that near-dormant capsular Dlk1+ cells are re-activated during ZF regeneration to become steroidogenic cells. Taken together, our results provide evidence for a role of DLK1+ cells as contributors to the development and zonation of the adrenal cortex.