Abstract Disclosure: V. Chortis: None. K. Dulanjalee: None. N.A. Guagliardo: None. M.S. Shah: None. R. Claudio: None. P.Q. Barrett: None. K.S. Borges: None. D.L. Carlone: None. D.T. Breault: None. Fibroblast Growth Factor Receptors (FGFRs) are tyrosine kinase receptors with critical roles in organogenesis and tissue homeostasis. We have recently shown that Fgfr2 deletion in the outermost zone of the mouse adrenal cortex (zona Glomerulosa, zG) during post-natal development leads to disordered morphology. Interestingly, Fgfr2 is up-regulated in the zG of mice with adrenal hyperplasia due to constitutive activation of Wnt/beta-catenin signaling. Here, we seek to delineate the role of FGFR2 in adrenal morphology and function during postnatal development, adulthood homeostasis, as well as during β-catenin-induced adrenal hyperplasia. To address this, we used i) a mouse model of conditional Fgfr2 loss (Fgfr2-cKO), in which zG-specific Fgfr2 deletion begins during early post-natal development, and ii) an inducible mouse model (Fgfr2-icKO), in which Fgfr2 deletion in the zG during adult life is tamoxifen-dependent. Fgfr2 loss in Fgfr2-cKO mice disrupted zG cell differentiation in steroidogenically mature cells and limited their capacity to proliferate and undergo trans-differentiation into the adjacent zona Fasciculata. zG cell de-differentiation was also evident upon acute loss of Fgfr2 in adult Fgfr2-icKO mice. Furthermore, Fgfr2 loss in a mouse model of beta-catenin-induced zG hyperplasia was sufficient to fully abrogate adrenal hyperplasia. Treatment with pan-FGFR small molecule inhibitors suppressed cellular proliferation in the mouse zG and inhibited aldosterone secretion. Taken together, these results suggest FGFR2 has a critical role in normal adrenal development and tissue homeostasis and is an essential mediator of beta-catenin-induced adrenal hyperplasia. FGFR2 targeting may be meaningful in patients with conditions associated with aldosterone excess. Presentation: Thursday, June 15, 2023