7887 Non-Canonical Wnt Signaling Via WNT2B Is Critical For Adrenal Morphogenesis and Aldosterone Production
Authors: Borges Kleiton Silva , Little Donald W , de Almeida Magalhães Taciani , Ribeiro Claudio , Basham Kaitlin , Dumonte Typhanie 4 , Azova Svetlana , O’Connell Amy E , Guagliardo Nick A , Barrett Paula Q , Berber Mesut , Mohan Dipika , Turcu Adina , Rainey William , Lerario Antonio Marcondes , Carlone Diana L , Salic Adrian , Breault David T , Hammer Gary D 
Published: October 2024

Disclosure: K.S. Borges: None. D.W. Little III: None. T. de Almeida Magalhães: None. C. Ribeiro: None. K. Basham: None. T. Dumonte: None. S. Azova: None. A.E. O’Connell: None. N.A. Guagliardo: None. P.Q. Barrett: None. M. Berber: None. D. Mohan: None. A. Turcu: None. W. Rainey: None. A.M. Lerario: None. D.L. Carlone: None. A. Salic: None. D.T. Breault: None. G.D. Hammer: None.

The steroid hormone aldosterone, produced by the zona glomerulosa (ZG) of the adrenal gland, plays a key role in regulating plasma electrolyte levels and blood pressure. ZG dysregulation, the major driver of primary aldosteronism (PA), is a leading cause of hypertension marked by excessive aldosterone production. Conversely, ZG dysregulation also plays a role in congenital hypoaldosteronism (hypoA), characterized by insufficient aldosterone production. The signaling pathways governing ZG morphogenesis, including Wnt signaling, and their role in PA and hypoA remain poorly understood. Recent genome-wide association studies revealed a strong risk association between a heterozygous intronic variant in WNT2B and PA; whether this variant alters the expression of WNT2B is unknown. Interestingly, we discovered that patients harboring homozygous or compound heterozygous loss-of-function (LOF) mutations in WNT2B exhibit elevated plasma renin levels consistent with a primary defect in aldosterone production. To further characterize WNT2B signaling in the adrenal cortex, we analyzed mouse adrenals using single molecule in situ hybridization, which revealed expression of Wnt2b exclusively in the adrenal capsule, the outermost mesenchymal layer of the adrenal cortex and an important signaling center for adrenal cortex zonation and maintenance. To explore mechanisms by which WNT2B might regulate aldosterone production, we generated Wnt2b knock-out (KO) mice, which exhibited: smaller adrenals, a near-complete absence of the histological ZG, and a markedly reduced number of aldosterone-producing cells. Wnt2b KO mice also showed increased plasma renin with compensated aldosterone levels, concordant with patients harboring WNT2B LOF mutations. Analysis of mouse adrenal slices, ex vivo, confirmed impaired aldosterone production, indicating a primary ZG defect. Surprisingly, pharmacological activation of canonical Wnt/β-catenin signaling using LiCl, in vivo, failed to restore ZG function in Wnt2b KO mice. Further mechanistic studies showed that while WNT2B does not activate canonical Wnt/β-catenin signaling, it does activate the Wnt/planar cell polarity (Wnt/PCP) pathway, through FZD3, FZD6 and ROR2 receptors, leading to activation of the small GTPase RhoA. Moreover, Wnt2b KO mice showed a loss of ZG rosette structures, in vivo, consistent with impaired Wnt/PCP signaling. Collectively, these findings demonstrate that WNT2B signals through the Wnt/PCP pathway to regulate ZG morphogenesis and aldosterone production in mice and humans.

Presentation: 6/1/2024