Rho-ROCK signaling and α-Catenin mediate β-Catenin-driven hyperplasia in the adrenal via adherens junctions

Abstract

How {beta}-Catenin ({beta}Cat) mediates tissue hyperplasia is poorly understood. To explore this, we employed the adrenal cortex as a model system given its stereotypical spatial organization and the important role {beta}Cat plays in homeostasis and disease. For example, excessive production of aldosterone by the adrenal cortex (primary aldosteronism, PA) constitutes a significant cause of cardiovascular morbidity, which has been associated with {beta}Cat gain-of-function ({beta}Cat-GOF). Adherens junctions (AJs) connect the actin cytoskeletons of adjacent zona Glomerulosa (zG) cells via a cadherin/{beta}Cat/-Catenin (Cat) complex and mediate aldosterone production. Whether {beta}Cat-GOF drives zG hyperplasia, a key feature of PA, via AJs is unknown. Here, we show that aldosterone secretagogues (K+, AngII) and {beta}Cat-GOF mediate AJ enrichment via Rho-ROCK-actomyosin signaling. In addition, Rho-ROCK inhibition leads to altered zG rosette morphology and decreased aldosterone production. Mice with zG-specific {beta}Cat-GOF demonstrate increased AJ formation and zG hyperplasia, which was blunted by Rho-ROCK inhibition and deletion of Cat. Further, analysis of human aldosterone-producing adenomas (APAs) revealed high levels of {beta}Cat expression were associated with increased membranous expression of K-Cadherin. Together, our findings identify Rho-ROCK signaling and Cat as key mediators of AJ enrichment and {beta}-Catenin-driven hyperplasia. One Sentence SummaryThis study demonstrates that {beta}-Catenin-driven hyperplasia in the adrenal cortex, a key feature of primary aldosteronism, is mediated through Rho-ROCK signaling and -Catenin-dependent stabilization of adherens junctions, with significant implications for patients with primary aldosteronism. HighlightsO_LIRho-ROCK signaling drives AJ enrichment in the adrenal C_LIO_LIROCK inhibition via fasudil blunts aldosterone production C_LIO_LI{beta}Cat drives adrenal hyperplasia via enhanced AJ enrichment C_LIO_LIROCK inhibition or [a]Cat deletion block zG hyperplasia C_LI