Impaired steroid hormone production has been linked to poor reproductive health and congenital anomalies;therefore, proper differentiation of steroidogenic lineages is of paramount importance. Although structurally and functionally distinct, the major steroid-producing organs, the gonads and adrenal cortex, arise from a common pool of progenitors in the urogenital ridge. Despite extensive investigation, the factors that determine whether a steroidogenic cell precursor adopts a gonadal or adrenocortical phenotype are not understood. In the proposed studies, we will utilize novel mouse models of altered cell fate determination to examine the molecular basis of normal and pathological steroidogenic cell development. We will focus on transcription factor GATA-4, a key arbiter of steroidogenic cell fate. In mice, GATA-4 is expressed in sex steroid-producing cells of the gonad, but not in corticoid-producing cells of the adult adrenal. Changes in the expression of GATA-4 appear to influence the phenotype of steroidogenic cells. In preliminary experiments, we have found that targeted mutagenesis of Gata4 is associated with a defect in the differentiation of sex steroidogenic lineages;conversely, ectopic expression of this transcription factor can transform adrenocortical cells into tissue resembling gonadal stroma. We hypothesize that GATA-4, working in concert with gonadotropins and other hormones, determines the functional identity of steroidogenic cells.
Three specific aims will be pursued.
Aim 1 will examine the impact of GATA-4 deficiency on the differentiation of sex steroidogenic cells in ES cell-derived teratomas and embryoid bodies.
In Aim 2, we will assess the role of GATA-4 in sex steroidogenesis using chimeric mice.
In Aim 3, we will determine the effect of forced expression of GATA-4 on differentiation of adrenocortical cells in transgenic mice. These studies should shed light on the molecular basis of normal and pathological steroidogenic cell development.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
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Margolis, Ronald N
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Washington University
Schools of Medicine
Saint Louis
United States
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Penny, Gervette M; Cochran, Rebecca B; Pihlajoki, Marjut et al. (2017) Probing GATA factor function in mouse Leydig cells via testicular injection of adenoviral vectors. Reproduction 154:455-467
Dörner, Julia; Martinez Rodriguez, Verena; Ziegler, Ricarda et al. (2017) GLI1+ progenitor cells in the adrenal capsule of the adult mouse give rise to heterotopic gonadal-like tissue. Mol Cell Endocrinol 441:164-175
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Schrade, Anja; Kyrönlahti, Antti; Akinrinade, Oyediran et al. (2015) GATA4 is a key regulator of steroidogenesis and glycolysis in mouse Leydig cells. Endocrinology 156:1860-72
Pihlajoki, Marjut; Gretzinger, Elisabeth; Cochran, Rebecca et al. (2013) Conditional mutagenesis of Gata6 in SF1-positive cells causes gonadal-like differentiation in the adrenal cortex of mice. Endocrinology 154:1754-67
Parviainen, Helka; Schrade, Anja; Kiiveri, Sanne et al. (2013) Expression of Wnt and TGF-? pathway components and key adrenal transcription factors in adrenocortical tumors: association to carcinoma aggressiveness. Pathol Res Pract 209:503-9
Schillebeeckx, Maximiliaan; Schrade, Anja; Löbs, Ann-Kathrin et al. (2013) Laser capture microdissection-reduced representation bisulfite sequencing (LCM-RRBS) maps changes in DNA methylation associated with gonadectomy-induced adrenocortical neoplasia in the mouse. Nucleic Acids Res 41:e116

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