Loss of SUMO-specific protease 2 causes isolated glucocorticoid deficiency by blocking adrenal cortex zonal transdifferentiation in mice

The murine adrenal cortex is a constantly self-renewed endocrine organ composed of concentric zones, including the outermost zona glomerulosa (zG) producing mineralocorticoids and the innermost zona fasciculata (zF) producing glucocorticoids. According to the centripetal migration model occurring during postnatal development, progenitor cell populations located in the adrenal capsule or within the zG, consecutively differentiate into steroid-producing zG cells, then through a process of zonal transdifferentiation, convert into zF cells, and eventually undergo apoptosis at the corticomedullary junction (1, 2). Genetic models in mouse and in vitro approaches have identified two important signaling pathways for adrenal cortex homoeostasis. On the one hand, the WNT/Rspondin/β-catenin pathway is necessary for the maintenance of progenitor pools and the acquisition of zG identity (3, 4). On the other hand, cAMP/PKA signaling, following stimulation by the ACTH, triggers the recruitment of progenitors by inducing transdifferentiation of zG cells into zF cells and stimulates glucocorticoid production (5). The mechanisms that maintain adrenal cortex zonation and balance between these two pathways have not been elucidated yet.