Conditional Mutagenesis of Gata6 in SF1-Positive Cells Causes Gonadal-Like Differentiation in the Adrenal Cortex of Mice

Abstract

Transcription factor GATA6 is expressed in the fetal and adult adrenal cortex and has been implicated in steroidogenesis. To characterize the role of transcription factor GATA6 in adrenocortical development and function, we generated mice in which Gata6 was conditionally deleted using Cre-LoxP recombination with Sf1-cre. The adrenal glands of adult Gata6 conditional knockout (cKO) mice were small and had a thin cortex. Cytomegalic changes were evident in fetal and adult cKO adrenal glands, and chromaffin cells were ectopically located at the periphery of the glands. Corticosterone secretion in response to exogenous ACTH was blunted in cKO mice. Spindle-shaped cells expressing Gata4, a marker of gonadal stroma, accumulated in the adrenal subcapsule of Gata6 cKO mice. RNA analysis demonstrated the concomitant upregulation of other gonadal-like markers, including Amhr2, in the cKO adrenal glands, suggesting that GATA6 inhibits the spontaneous differentiation of adrenocortical stem/progenitor cells into gonadal-like cells. Lhcgr and Cyp17 were overexpressed in the adrenal glands of gonadectomized cKO vs control mice, implying that GATA6 also limits sex steroidogenic cell differentiation in response to the hormonal changes that accompany gonadectomy. Nulliparous female and orchiectomized male Gata6 cKO mice lacked an adrenal X-zone. Microarray hybridization identified Pik3c2g as a novel X-zone marker that is downregulated in the adrenal glands of these mice. Our findings offer genetic proof that GATA6 regulates the differentiation of steroidogenic progenitors into adrenocortical cells.

Genomic Analysis of Sexual Dimorphism of Gene Expression in the Mouse Adrenal Gland

“…The physiological role of the X-zone, which may be partially restored after castration of adult male mice, is unknown, but it was shown to express specifi cally the progesterone-metabolizing enzyme 20α-hydroxysteroid dehydrogenase (20α-HSD; Akr1c18) [ 15 ] . More recently, the phosphoinositide kinase Pik3c2g has also been shown to be expressed specifi cally in the X-zone in the mouse adrenal cortex [ 16 ] . A remarkable fi nding of our study is the identifi cation of genes whose expression is high in female adrenals, downregulated in females after testosterone treatment and upregulated in males after castration.…”

PKA signaling drives reticularis differentiation and sexually dimorphic adrenal cortex renewal

“…We next carried out qPCR analyses to measure time-dependent expression of 2 X-zone markers (Akr1c18, encoding 20αHSD, and Pik3c2g, ref. 25) during expansion of the fetal-like zone in DAdKO females and spontaneous regression of the X-zone in controls (which occurs at ~5 months in virgin females, ref. 7).…”

Luteinizing Hormone and GATA4 Action in the Adrenocortical Tumorigenesis of Gonadectomized Female Mice

“…On the other hand, GATA6, another member of the GATA transcription factor family, regulates adrenal steroidogenic cell differentiation [10]. Interestingly, the interplay between GATA6 and GATA4 transcription factors in adrenal pathophysiology has been suggested to determine the cell fate [10-13].…”

“…On the other hand, GATA6, another member of the GATA transcription factor family, regulates adrenal steroidogenic cell differentiation [10]. Interestingly, the interplay between GATA6 and GATA4 transcription factors in adrenal pathophysiology has been suggested to determine the cell fate [10-13]. The lack of GATA6 in the adrenal gland promotes A cell formation [10], whereas GATA4 is pivotal for adrenal tumor onset in DBA/2J and 21-OH-GATA-4 mice [6, 14, 15].…”

“…Interestingly, the interplay between GATA6 and GATA4 transcription factors in adrenal pathophysiology has been suggested to determine the cell fate [10-13]. The lack of GATA6 in the adrenal gland promotes A cell formation [10], whereas GATA4 is pivotal for adrenal tumor onset in DBA/2J and 21-OH-GATA-4 mice [6, 14, 15]. Additionally, in Inha -/- mouse model, it has been proposed that the development of tumorous and gonadal-like phenotypes of adrenal tumors is a consequence of the switch from GATA6 to GATA4 expression triggered by elevated gonadotropins [9].…”