Steroidogenic Factor 1 and Beta-Catenin: Two Critical Regulators of Endocrine Organ Development

The endocrine system comprises a diverse array of organs and hormones that regulate many aspects of development and homeostasis. Steroidogenic hormones - secreted by the adrenal cortex, testis, and ovary - are required for electrolyte balance, maintenance of intermediary metabolism, and reproduction. The nuclear receptor steroidogenic factor 1 (SF-1, officially designated NR5A1) originally was identified as a transcriptional regulator of steroidogenic synthetic enzymes. In addition to expression in the adrenal cortex and somatic cells of the gonads, however, SF-1 is expressed in the ventromedial hypothalamic nucleus (VMH) and pituitary gonadotropes, suggesting a broader role in endocrine physiology. Global knockout of SF-1 in mice confirmed this possibility, as it resulted in complete adrenal and gonadal agenesis and XY sex reversal, causing postnatal death due to adrenal insufficiency. Humans with mutations in SF-1 exhibit a spectrum of phenotypes ranging from 46, XY sex reversal and adrenal insufficiency to patients with normal adrenal function and mild gonadal dysgenesis. Herein is reported a patient with compound heterozygosity for a previously described SF-1 polymorphism and a novel mutation, p.R84C, which impairs DNA binding and transactivation activity. SF-1 interacts with numerous coactivators, including beta-catenin, a central mediator of the canonical Wnt signaling pathway. Upon activation by Wnt, beta-catenin translocates to the nucleus where it enhances the transcription of Wnt target genes, and - as recently appreciated - a subset of SF-1 gene targets. Due to the reported functional synergy between SF-1 and beta-catenin, and as Wnt4 deficiency in mice resulted in adrenal and gonadal defects, we investigated the consequences of beta-catenin disruption in certain SF-1-expressing tissues, specifically the adrenal and pituitary glands, and the VMH. SF-1/Cre-mediated beta-catenin knockout mice died immediately after birth and lacked adrenal glands. In contrast, the VMH and pituitary gland were largely unaffected from a structural viewpoint. Analysis of adrenal development revealed that though the adrenal primordium forms, adrenocortical cell numbers quickly decline due to impaired proliferation. The potential for beta-catenin/SF-1 synergy on a fetal adrenal specific enhancer was investigated. These results implicate beta-catenin - presumably as part of the Wnt signaling pathway - as a required factor in adrenocortical development.