Abstract
How β-Catenin (βCat) 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 βCat 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 βCat gain-of-function (βCat-GOF). Adherens junctions (AJs) connect the actin cytoskeletons of adjacent zona Glomerulosa (zG) cells via a cadherin/βCat/α-Catenin (αCat) complex and mediate aldosterone production. Whether βCat-GOF drives zG hyperplasia, a key feature of PA, via AJs is unknown. Here, we show that aldosterone secretagogues (K (+) , AngII) and βCat-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 βCat-GOF demonstrate increased AJ formation and zG hyperplasia, which was blunted by Rho-ROCK inhibition and deletion of αCat. Further, analysis of human aldosterone-producing adenomas (APAs) revealed high levels of βCat expression were associated with increased membranous expression of K-Cadherin. Together, our findings identify Rho-ROCK signaling and αCat as key mediators of AJ enrichment and β-Catenin-driven hyperplasia. ONE SENTENCE SUMMARY: This study demonstrates that β-Catenin-driven hyperplasia in the adrenal cortex, a key feature of primary aldosteronism, is mediated through Rho-ROCK signaling and α-Catenin-dependent stabilization of adherens junctions, with significant implications for patients with primary aldosteronism. HIGHLIGHTS: Rho-ROCK signaling drives AJ enrichment in the adrenalROCK inhibition via fasudil blunts aldosterone productionβCat drives adrenal hyperplasia via enhanced AJ enrichmentROCK inhibition or ɑCat deletion block zG hyperplasia.