Endocrine Abstracts

Background: The adrenal gland produces corticosteroids essential for hydromineral and metabolic homeostasis. It is organised, in mice, in two concentric layers. The zona glomerulosa (zG) and fasciculate (zF), renewed from progenitors located in the capsular periphery. Centripetal renewal and maintenance of cortical zonation are dependant of a balance between WNT/β-catenin and ACTH/PKA signalling pathways. They provide recruitment and consecutive differentiation of progenitors into zG and zF. In the adrenal cortex, zG to zF blockage caused by loss of Senp2 is associated with over expression of Prader-Willi imprinted genes Ndn and Magel2. This is similar to the loss of SENP2 in brown preadipocytes, where Ndn is upregulated and prevent brown adipocyte differentiation. Ndn and Magel2 are implicated in Prader Willi syndrome, a complex genetic disorder affecting multiple endocrine organ and possibly the hypothalamus-pituitary-adrenal axis (HPA).

Objectives: Evaluate the contribution of NDN and MAGEL2 in HPA physiology and response to stress.

Methods: We investigated NDN expression in the adrenal and under several genetic and pharmacologic stimulations. We then submitted Ndn-/- Magel2-/- mice to mild stress and explored the HPA physiology through measurement of peptides and steroid hormones.

Results: We found expression of NDN restricted to the zG in the adrenal and negatively regulated by ACTH via PKA signalling. We show that even though NDN and MAGEL2 loss does not lead to morphological changes, their deletion induces blunted stress response and leads to accumulation of ACTH precursor Pomc in the pituitary.

Conclusion: We can conclude that NDN and MAGEL2 are important actors of proper response to stress. Conditional models targeting the pituitary will lead to better understanding of the mechanisms at stake.