Adrenal gland differentiation: positive antagonism

Adrenal gland differentiation: positive antagonism

Endocrine activity of the adrenal glands is essential for body homeostasis and depends on the differentiation of two concentric cellular zones. Using transgenic mouse models, Pierre Val’s team has shown that this zonal differentiation relies on a double antagonistic interaction between two signalling pathways. They further show that this antagonism inhibits development of aggressive tumours in mouse models and patients. This study is published in Nature Communications (Drelon et al., 2016) .

Adrenal glands are endocrine tissues situated above each kidney. They constitute the main stress response organ and are composed of two distinct tissues. The centre of the gland is occupied by adrenal medulla, which synthesizes adrenalin. The periphery is composed of the adrenal cortex, involved in the production of corticosteroids such as cortisol (natural equivalent to cortisone, which is one of the most frequent anti-inflammatory prescription) and aldosterone. Lack of adrenal steroid production is a life-threatening condition. At the other end of the spectrum, increased corticosteroid production is associated with profound metabolic disruption (obesity and muscle loss) and severe hypertension. Normal adrenal cortex endocrine activity relies on coordinated development of the gland, which is characterised by establishment of distinct concentric cellular zones. The external zone or zona glomerulosa is characterised by cell organisation as rosettes, in charge of aldosterone production. The internal zone, or zona fasciculata is organised in cellular cords, responsible for the production of cortisol.

Adrenal cortex cells are constantly renewed throughout life. After division, cells residing in the periphery of the gland migrate inwards and initially differentiate as glomerulosa cells. They further move inside the cortex and change identity to become zona facsiculata cells. Despite this continuous flow of cells, the boundary between the two zones and tissue organisation are stable. This observation suggests that cells receive positional cues instructing their differentiation as glomerulosa or fasciculata as a function of their localisation within the tissue.

Using combinations of genetically engineered mice, GReD researchers demonstrated that establishment and maintenance of the two functional zones relied on two distinct cell signalling pathways: WNT/b-catenin pathway, which is activated in zona glomerulosa and protein kinase A (PKA), activated in zona fasciculata. Activation of WNT signalling relies on WNT4, a diffusible ligand expressed in the outer cortex. This activation inhibits PKA signalling pathway, which locks cells in glomerulosa identity. As cells move away from the source of WNT4 ligand along migration, they become capable of responding to PKA signalling which then blocks WNT pathway activation. This locks cells in fasciculata identity.

The team had previously shown that abnormal WNT pathway activation resulted in development of benign and malignant tumours of the adrenal cortex, both in mouse models and in patients. Elaborating on their observations on adrenal differentiation, the researchers have shown that PKA also blocks WNT signalling in the context of tumourigenesis. Indeed, when PKA pathway activity is reduced in transgenic mice, WNT pathway activation results in rapid development of aggressive adrenal tumours. These data on mouse models have further been confirmed in patients with adrenocortical cancer by analysis of gene expression data from the cancer genome atlas consortium.

This work has been highlighted on the CNRS website (in French)

For more informations ….

PKA inhibits WNT signalling in adrenal cortex zonation and prevents malignant tumour development.

Drelon C, Berthon A, Sahut-Barnola I, Mathieu M, Dumontet T, Rodriguez S, Batisse-Lignier M, Tabbal H, Tauveron I, Lefrançois-Martinez AM, Pointud JC, Gomez-Sanchez CE, Vainio S, Shan J, Sacco S, Schedl A, Stratakis CA, Martinez A, Val P.

Nat Commun. 2016 Sep 14;7:12751. doi: 10.1038/ncomms12751.


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Last modified: 01/24/2017