title: Anti-Müllerian hormone regulation by the bone morphogenetic proteins in the sheep ovary: deciphering a direct regulatory pathway.
abstract: In the ovary, anti-Müllerian hormone (AMH) is produced by the granulosa cells of growing follicles and can modulate the recruitment of primordial follicles and the FSH-dependent development of follicles. However, the regulation of its production remains poorly understood. Recently, a stimulating effect of the bone morphogenetic proteins (BMPs) on AMH production by granulosa cells has been shown in vitro, but the molecular mechanisms implicated in this regulation and its physiological importance in ovarian function have not yet been established. In the hyperprolific Booroola ewes carrying the FecB(B) partial loss-of-function mutation in the fecundity gene encoding the FecB/BMP receptor, type 1B, the granulosa cells of antral follicles expressed and secreted low AMH amounts, resulting in low AMH concentrations in blood, despite high numbers of AMH-secreting follicles in ovaries. The presence of the FecB(B) mutation impaired the granulosa cell response to the stimulating action of BMP4 on AMH production, indicating a crucial role of the BMP receptor, type 1B in AMH regulation. In ovine granulosa cells, BMP4 enhanced the transcriptional activity of the human AMH promoter, and this action depended on the presence of SMAD1, acting on a promoter sequence located between -423 and -202 bp upstream of the AMH transcription start site. SMAD1 and SF1 acted in concert to mediate BMP4 action on the AMH promoter. Among the 2 SF1 binding sites present on the AMH promoter, the most proximal site, located at -92 bp upstream of the AMH transcription start site, was found to be critical for ensuring the response of the AMH promoter to BMP4. In conclusion, AMH could mediate the actions of BMPs in regulating follicular development and contributing to the determination of ovulation numbers. A molecular model of regulation of the AMH promoter transactivation by BMP signaling is proposed.
authors.affiliation: INRA (A.E., P.J., C.M., D.M.), UMR85 Physiologie de la Reproduction et des Comportements; CNRS, UMR7247; and Université François Rabelais de Tours, F-37041 Tours and IFCE, F-37380 Nouzilly, France; Université Paris Diderot (A.P., N.d.C., J.-Y.P.), Sorbonne Paris Cité; Inserm U1133, Physiologie de l'Axe Gonadotrope; and CNRS, UMR8251, Biologie Fonctionnelle et Adaptative, F-75013 Paris, France; and INRA (S.F.), UMR1388 Génétique, Physiologie et Système d'Elevage (GenPhySE) and Université de Toulouse, INP, ENSAT, GenPhySE, F-31326 Castanet-Tolosan and Université de Toulouse, INP, ENVT, GenPhySE, F-31076 Toulouse, France.
authors.forename: Anthony
authors.initials: A
authors.lastname: Estienne
authors.forename: Alice
authors.initials: A
authors.lastname: Pierre
authors.forename: Nathalie
authors.initials: N
authors.lastname: di Clemente
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Picard
authors.forename: Peggy
authors.initials: P
authors.lastname: Jarrier
authors.forename: Camille
authors.initials: C
authors.lastname: Mansanet
authors.forename: Danielle
authors.initials: D
authors.lastname: Monniaux
authors.forename: Stéphane
authors.initials: S
authors.lastname: Fabre
mesh_terms: D000818:Animals; D054304:Anti-Mullerian Hormone / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D005838:Genotype; D006107:Granulosa Cells / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012756:Sheep / Q000502:physiology*; D014162:Transfection
chemical_list: D055415:Bone Morphogenetic Protein 4; D012333:RNA, Messenger; D054304:Anti-Mullerian Hormone; D052005:Bone Morphogenetic Protein Receptors, Type I