Regulation of Adrenocortical Morphogenesis and Function by WNT and FGF Signaling

Abstract

How morphology informs function has long been a topic of fascination in biology. In an adult organ, highly specialized cell types function together in microenvironments that are often drastically different depending on the anatomical location of the organ. However, little is known about how different morphological features can influence diverse cellular functions. The adrenal cortex is an ideal model to study this question. As part of the mammalian endocrine system, the adult cortex consists of concentric layers of tissue termed “zones”. Each zone produces distinct steroid hormones and adopts a unique morphology. The mechanisms governing the formation of these morphological features and their functional significance are unknown. In this dissertation, we first examine the morphological features of the outer layer, zona glomerulosa (zG), and identify cellular and molecular mechanisms governing its formation. We show mature adrenal glomeruli consist of rosettes, a multicellular structure widely used in epithelial remodeling during development. Furthermore, rosette formation underlies a previously unknown process of postnatal glomerular morphogenesis. β-catenin, an integral component of the adherens junction and key transducer of canonical WNT signaling, is a potent regulator of glomerular morphology. β-catenin stabilization leads to increased FGFR2. Deletion of Fgfr2 results in altered adherens junction stability and distribution, leading to decreased rosette frequency and disruption of glomerular morphology. Next, we investigate the impact of WNT and FGF signaling modulation on zG physiological function. β-catenin stabilization causes zG hyperplasia due to a block of zonal transdifferentiation, concurrent with increased aldosterone and elevated blood pressure. In contrast, Fgfr2 deletion results in suppressed zG function, as evident by loss of Cyp11b2 expression and increased plasma renin activity, a compensatory response to insufficient aldosterone output. Moreover, pharmacological inhibition of FGFR2 effectively lowers aldosterone production and zG proliferation, demonstrating the therapeutic potential of FGFR2 inhibition in treating hyperaldosteronism and adrenal hyperplasia. Together, this dissertation provides fundamental insights into how the adrenal zG acquires its form. We show the WNT and FGF signaling pathways are important regulators of zG morphology and function. Our findings provide a conceptual framework for future studies on the link between zG tissue morphology and function.