title: Combined loss of the GATA4 and GATA6 transcription factors in male mice disrupts testicular development and confers adrenal-like function in the testes.
abstract: The roles of the GATA4 and GATA6 transcription factors in testis development were examined by simultaneously ablating Gata4 and Gata6 with Sf1Cre (Nr5a1Cre). The deletion of both genes resulted in a striking testicular phenotype. Embryonic Sf1Cre; Gata4(flox/flox) Gata6(flox/flox) (conditional double mutant) testes were smaller than control organs and contained irregular testis cords and fewer gonocytes. Gene expression analysis revealed significant down-regulation of Dmrt1 and Mvh. Surprisingly, Amh expression was strongly up-regulated and remained high beyond postnatal day 7, when it is normally extinguished. Neither DMRT1 nor GATA1 was detected in the Sertoli cells of the mutant postnatal testes. Furthermore, the expression of the steroidogenic genes Star, Cyp11a1, Hsd3b1, and Hsd17b3 was low throughout embryogenesis. Immunohistochemical analysis revealed a prominent reduction in cytochrome P450 side-chain cleavage enzyme (CYP11A1)- and 3β-hydroxysteroid dehydrogenase-positive (3βHSD) cells, with few 17α-hydroxylase/17,20 lyase-positive (CYP17A1) cells present. In contrast, in postnatal Sf1Cre; Gata4(flox/flox) Gata6(flox/flox) testes, the expression of the steroidogenic markers Star, Cyp11a1, and Hsd3b6 was increased, but a dramatic down-regulation of Hsd17b3, which is required for testosterone synthesis, was observed. The genes encoding adrenal enzymes Cyp21a1, Cyp11b1, Cyp11b2, and Mcr2 were strongly up-regulated, and clusters containing numerous CYP21A2-positive cells were localized in the interstitium. These data suggest a lack of testis functionality, with a loss of normal steroidogenic testis function, concomitant with an expansion of the adrenal-like cell population in postnatal conditional double mutant testes. Sf1Cre; Gata4(flox/flox) Gata6(flox/flox) animals of both sexes lack adrenal glands; however, despite this deficiency, males are viable in contrast to the females of the same genotype, which die shortly after birth.
authors: Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida 32610.
authors: Maria B
authors: MB
authors: Padua
authors: Tianyu
authors: T
authors: Jiang
authors: Deborah A
authors: DA
authors: Morse
authors: Shawna C
authors: SC
authors: Fox
authors: Heather M
authors: HM
authors: Hatch
authors: Sergei G
authors: SG
authors: Tevosian
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D054304:Anti-Mullerian Hormone / Q000235:genetics / Q000378:metabolism; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics / Q000378:metabolism; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics / Q000378:metabolism; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000502:physiology*; D050993:GATA6 Transcription Factor / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D008297:Male; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics / Q000378:metabolism; D013255:Steroid 21-Hydroxylase / Q000235:genetics / Q000378:metabolism; D013737:Testis / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: C110547:DMRT1 protein; D050991:GATA4 Transcription Factor; D050993:GATA6 Transcription Factor; C484171:Gata4 protein, mouse; C494760:Gata6 protein, mouse; D010750:Phosphoproteins; D012333:RNA, Messenger; D014157:Transcription Factors; D000098682:Steroidogenic Acute Regulatory Protein; D054304:Anti-Mullerian Hormone; D015067:17-Hydroxysteroid Dehydrogenases; D015096:3-Hydroxysteroid Dehydrogenases; C531511:Cyp21a1 protein, mouse; D013255:Steroid 21-Hydroxylase; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase; D002786:Cholesterol Side-Chain Cleavage Enzyme