ROR1/ROR2 regulate aldosterone production from the zona glomerulosa

Adrenal morphogenesis and aldosterone production depend on tightly regulated signaling pathways. While β-catenin (βCat)-dependent Wnt signaling in the zona glomerulosa (zG) has been extensively studied, the role of βCat-independent Wnt signaling remains poorly defined. Emerging evidence indicates that βCat-independent Wnt signaling also regulates zG cells and that genetic variants in associated loci are linked to aldosterone dysregulation, including hypoaldosteronism and primary aldosteronism. βCat-independent Wnt signaling acts through distinct transmembrane co-receptors, including the ROR family proteins (receptor tyrosine kinase-like orphan receptors 1 and 2, ROR1/2). To determine whether signaling via these co-receptors regulates adrenal morphogenesis and/or aldosterone production, we employed zG-specific ROR1/2 knockout mice. Our results showed that ROR1/2 were dispensable for zG formation and size but were required for normal zG adherens junction integrity. In addition, ROR1/2 were important for transdifferentiation of zG cells into zona fasciculata cells and zG cell survival. Finally, ROR1/2 were important for overall levels of Cyp11b2 expression and aldosterone production. Taken together, these results identified an important role for ROR1/2-dependent signaling, in the regulation of zG function and maintenance of aldosterone production and suggest its dysregulation may contribute to hypoaldosteronism and primary aldosteronism.