title: 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.
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
authors.forename: Marjut
authors.initials: M
authors.lastname: Pihlajoki
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Gretzinger
authors.forename: Rebecca
authors.initials: R
authors.lastname: Cochran
authors.forename: Antti
authors.initials: A
authors.lastname: Kyrönlahti
authors.forename: Anja
authors.initials: A
authors.lastname: Schrade
authors.forename: Theresa
authors.initials: T
authors.lastname: Hiller
authors.forename: Laura
authors.initials: L
authors.lastname: Sullivan
authors.forename: Michael
authors.initials: M
authors.lastname: Shoykhet
authors.forename: Erica L
authors.initials: EL
authors.lastname: Schoeller
authors.forename: Michael D
authors.initials: MD
authors.lastname: Brooks
authors.forename: Markku
authors.initials: M
authors.lastname: Heikinheimo
authors.forename: David B
authors.initials: DB
authors.lastname: Wilson
mesh_terms: D000302:Adrenal Cortex / Q000166:cytology* / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D054338:Cell Transdifferentiation / Q000235:genetics*; D005260:Female; D005298:Fertility / Q000235:genetics; D050993:GATA6 Transcription Factor / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D006066:Gonads / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D054339:Steroidogenic Factor 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D050993:GATA6 Transcription Factor; C494760:Gata6 protein, mouse; D054339:Steroidogenic Factor 1; C515058:steroidogenic factor 1, mouse