Steroidogenic factor-1 controls the aldose reductase akr1b7 gene promoter in transgenic mice through an atypical binding site.
Aldo-keto-reductase 1B7/mouse vas deferens protein (AKR1B7/MVDP) is expressed in rodent steroidogenic glands and in the mouse vas deferens. In steroidogenic organs, AKR1B7/MVDP scavenges isocaproaldehyde produced from the cholesterol side-chain cleavage reaction. Akr1b7/mvdp is responsive to ACTH in adrenals and to androgens in vas deferens. Using transgenic mice, we previously delimited the regulatory DNA sequences necessary for expression in both organs and identified by cell transfections, a cryptic steroidogenic factor-1 (SF-1) response element (SFRE) at -102 that overlaps a proximal androgen-responsive element. To address its in vivo functions in adrenals, we devised a transgenic mouse study using wild-type and mutant akr1b7 promoters driving the chloramphenol acetyltransferase reporter gene. Adrenal expression in adults was impaired in all lines mutant for -102 SFRE. This effect is linked to impaired SF-1 binding and not to impaired androgen receptor binding, because akr1b7 expression is not affected in adrenals of androgen receptor-defective Tfm mice. Triphasic developmental patterns of both AKR1B7 and wild-type transgene expression paralleled changes in SF-1 levels/binding activity; expression was maximal in late embryos, minimal in 6- to 15-d-old neonates, and thereafter progressively restored. Differences in developmental expression between wild-type and mutant transgenes revealed that requirement for the -102 SFRE appears stage specific, as its integrity is an absolute prerequisite for reinduction of gene expression after postnatal d 15. Further, mutation of this site did not affect transgene responsiveness to ACTH. These findings demonstrate a new function for SFRE in vivo, via influencing promoter sensibility to postnatal changes of SF-1 contents, in controlling promoter strength in adults without affecting adrenal targeting, hormonal control, or early gene expression.
Martinez
Antoine
A
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6547, Génétique des Eucaryotes and Endocrinologie Moléculaire, Université Blaise Pascal, 63177 Aubière, France. antoine.martinez@geem.univ-bpclermont.fr
Val
Pierre
P
Sahut-Barnola
Isabelle
I
Aigueperse
Christelle
C
Veyssière
Georges
G
Lefrançois-Martinez
Anne-Marie
AM
D000311:Adrenal Glands / Q000254:growth & development / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000449:Aldehyde Reductase; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology; D051717:Fushi Tarazu Transcription Factors; D018507:Gene Expression Regulation, Developmental; D005938:Glucocorticoids / Q000494:pharmacology; D018398:Homeodomain Proteins; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000502:physiology*; D011506:Proteins / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D054339:Steroidogenic Factor 1; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D004268:DNA-Binding Proteins; D051717:Fushi Tarazu Transcription Factors; D005938:Glucocorticoids; D018398:Homeodomain Proteins; C431936:Nr5a2 protein, mouse; D011506:Proteins; D011944:Receptors, Androgen; D018160:Receptors, Cytoplasmic and Nuclear; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; C515058:steroidogenic factor 1, mouse; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; C066498:Akr1b7 protein, mouse; D000449:Aldehyde Reductase