ESPE Yearbook of Paediatric Endocrinology

Brief summary: This study investigates the role of SUMOylation in adrenal development and function

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.

SUMOylation is a dynamic posttranslational modification, which provides fine-tuning of protein function involved in the cellular response to stress, differentiation, and tissue development. In the adrenal cortex, the SUMOylation gradient is inversely correlated with the gradient of cellular differentiation raising important questions about its role in functional zonation and the response to stress (6). Therefore, the adrenal gland could provide a paradigm to study how SUMOylation dynamics can interact with the function and homoeostasis of an organ, which is in charge of constant adaptation to stress.

Considering that SUMO-specific protease 2 (SENP2), a deSUMOylating enzyme, is upregulated by ACTH/cAMP-PKA signaling within the zona fasciculata (20-21), the authors generated mouse models of adrenal hyperSUMOylation by conditional ablation of Senp2 in the cortex (Senp2cKO). Their results reveal that Senp2cKO mice show zone-specific adrenal atrophy, isolated glucocorticoid deficiency and blunted response to ACTH. Progressive atrophy of zF evoked by SENP2 deficiency results from a blockade of zonal transdifferentiation, early apoptosis and impaired PKA catalytic activity that cannot be rescued by genetic derepression of the PKA holoenzyme. SENP2-deficient adrenals also show increased β-catenin SUMOylation and activity that may help to antagonize PKA signaling, thus maintaining the suppression of zF identity. As Senp2 expression is itself under the control of ACTH/PKA, these data identify SUMOylation as a feedforward mechanism that readies the adrenal cortex to respond to stress and maintain functional zonation.

These findings highlight the central role of SUMOylation in physiological processes, such as differentiation, tissue maintenance, and stress response. They also suggest that genetic alterations leading to excessive SUMOylation could be associated with isolated glucocorticoid deficiency in patients.

References: 1. King P, Paul A, Laufer E. Shh signaling regulates adrenocortical development and identifies progenitors of steroidogenic lineages. Proc. Natl Acad. Sci. USA. 2009; 106:21185–21190. 2. Freedman BD, et al. Adrenocortical zonation results from lineage conversion of differentiated zona glomerulosa cells. Dev. Cell. 2013; 26:666–673. 3. Berthon A, et al. Constitutive beta-catenin activation induces adrenal hyperplasia and promotes adrenal cancer development. Hum. Mol. Genet. 2010; 19:1561–1576. 4. Berthon A, et al. WNT/beta-catenin signalling is activated in aldosterone-producing adenomas and controls aldosterone production. Hum. Mol. Genet. 2014; 23:889–905. 5. Dumontet, T. et al. PKA signaling drives reticularis differentiation and sexually dimorphic adrenal cortex renewal. JCI Insight3, 2018: e98394. 6. Chang H-M, Yeh ETH. SUMO: from bench to bedside. Physiol. Rev. 2020; 100:1599–1619.