Role of B-Catenin Signaling in Adrenocortical Development and Tumorigenesis

Abstract

Wnt/β-catenin signaling plays many important roles during mammalian development. In the adrenal cortex, perturbations in the signaling pathway are associated with abnormal development and adrenocortical tumorigenesis. Loss- and gain-of-function mutations in Wnt4 result in profound defects in embryonic specification of the mouse adrenal cortex, metanephric kidney, and gonad. Moreover, stabilization of β-catenin has been reported in sporadic adrenocortical carcinoma (ACC) as well as ACC associated with Gardner Syndrome. In order to gain further insights into the role of β-catenin in the adrenal gland development and tumorigenesis, we utilized a conditional knockout (KO) approach. Mice harboring homozygous floxed-β-catenin or floxed-APC alleles were crossed to transgenic mice containing adrenal specific Cre drivers (Sf1-Crelow and Sf1-Crehigh). Inactivation of β-catenin mediated by Sf1-Crehigh, a transgene expressed at high levels, caused adrenal aplasia in newborn mice. Analysis of fetal adrenal development with Sf1-Crehigh-mediated β-catenin inactivation showed decreased proliferation in presumptive adrenocortical precursor cells. In contrast, the Sf1-Crelow transgene effected a lesser degree of β-catenin inactivation that did not affect all adrenocortical cells, permitting adrenal survival to reveal age-dependent degeneration of the cortex. Conversely, to examine the role of constitutive activation of β-catenin, we performed conditional knockout of Apc alleles (Apchigh KO and Apclow KO) using an adrenal-specific Cre-expressing transgenic mice, Sf1-Crehigh and Sf1-Crelow. In Apchigh KO, we observe an abnormally developed adrenal that resembles an embryonic adrenal gland. These adrenals are small in size and never fully maturity. On the other hand, Apclow KO reveal an initial expansion of less differentiated aberrant cells. These cells exhibit high cytoplasmic and nuclear concentration of β-catenin, coincident with an increased proliferation. At >30 weeks of age, these mice presented with adrenocortical adenomas and later presented with adrenocortical carcinomas. These results define critical roles for β-catenin in both embryonic development of the adrenal cortex, in the adult organ maintenance, and tumorigenesis.