Testicular Steroidogenic Cells to the Rescue

In this issue of Endocrinology, Padua et al (1) characterize the phenotype of mice lacking both GATA4 and GATA6 in steroidogenic cells. The double-mutant mice are born with adrenal aplasia. The female pups die from adrenocortical insufficiency, but the males survive owing to ectopic corticoid production by adrenal-like cells in the testis. These mutant mice shed new light on the regulation of steroidogenic cell differentiation and may provide a model for the study of testicular adrenal rest tumors (TARTs). Steroidogenic cells in the adrenal cortex and testis arise from a common pool of progenitors in the adrenogonadal primordium (AGP), a specialized group of coelomic epithelial cells in the urogenital ridge (Figure 1) (2). Adrenocortical progenitors migrate medially and combine with sympathoblasts, the precursors of the medulla, to form the nascent adrenal gland, which begins to produce glucocorticoids and other steroids (3). Gonadal progenitors migrate laterally and combine with primordial germ cells to form the bipotential gonad. Expression of Sry in the male gonad triggers the differentiation of Sertoli cells, which nurture germ cells and secrete paracrine factors that promote the differentiation of steroidogenic Leydig cells (4). In addition to producing T that is crucial for masculinization of the male fetus, fetal Leydig cells secrete insulin like-3, a hormone that promotes testicular descent (5). The common developmental origin of the adrenal cortex and testis is reflected in overlapping functional profiles for these organs. For example, the testes of newborn mice contain interstitial cells that express adrenocortical differentiation markers (eg, Cyp21a1, Cyp11b1), and ACTH stimulates androgen and glucocorticoid production by this tissue (6–8). Conversely, the adrenal gland of the adult mouse harbors rare stem/progenitor cells that can differentiate into gonadal-like cells in response to the hormonal changes that accompany gonadectomy (9–11). Among the plethora of transcription factors implicated in the differentiation of adrenal or testicular steroidogenic cells, a few are indispensable (3, 12). The prototype of these is steroidogenic factor-1 (SF1; also called Ad4BP or NR5A1). Sf1 is expressed in the AGP, adrenocortical cells, Sertoli cells, and Leydig cells. Mice lacking SF1 exhibit defects in both adrenal and testicular development (13, 14). Because SF1 is expressed in all steroidogenic tissues, it cannot by itself account for functional differences between steroid-producing cells in the adrenal cortex and testis. Two members of the GATA transcription factor family, GATA4 and GATA6, also regulate steroidogenesis and have been shown to impact the balance between adrenal and gonadal differentiation (11). During fetal mouse development, Gata4 and Gata6 are coexpressed in adrenocortical cells, Sertoli cells, and Leydig cells (15, 16). After birth, Gata6 expression persists in the adrenal cortex and testis, but Gata4 expression wanes in the adrenal gland (15, 16). Mice harboring germline homozygous null mutations in either Gata4 or Gata6 die early in embryonic development, so Cre-LoxP technology has been used to investigate the roles of GATA4 and GATA6 in steroidogenic tissues (15). These studies have shown that GATA4 is required for genital ridge development, testicular morphogenesis, and fetal/adult Sertoli cell function (17–19). In contrast, loss of GATA6 in steroidogenic cells mainly impacts adrenocortical zonation and function (20). As detailed in this issue of Endocrinology, combined loss of GATA4 and GATA6