title: Role of Foxl2 in uterine maturation and function.
abstract: Foxl2 codes for a forkhead/HNF3 transcription factor essential for follicular maturation and maintenance of ovarian identity. FOXL2 mutations are associated with Blepharophimosis, Ptosis and Epicanthus inversus Syndrome (BPES) characterized by eyelid malformations (types I and II) and premature ovarian insufficiency (type I). We show that Foxl2 is not only expressed by the ovary, but also by other components of the mouse female reproductive tract, including the uterus, the cervix and the oviduct. In the uterus, Foxl2 expression is first observed in the neonatal mesenchyme and, during uterine maturation, persists in the stroma and in the deep inner myometrial layer (IML). In the adult, Foxl2 is expressed in the differentiated stromal layer, but no longer in the myometrium. Conditional deletion of Foxl2 in the postnatal (PN) uterus using Progesterone Receptor-cre (Pgr(cre/+)) mice results in infertility. During PN uterine maturation Pgr(cre/+); Foxl2(flox/flox) mice present a severely reduced thickness of the stroma layer and an hypertrophic, disorganized IML. In adult Pgr(cre/+); Foxl2(flox/flox) mice a supplementary muscular layer is present at the stroma/myometrium border and vascular smooth muscle cells fail to form a coherent layer around uterine arteries. Wnt signalling pathways play a central role in uterine maturation; in Pgr(cre/+); Foxl2(flox/flox) mice, Wnt genes are deregulated suggesting that Foxl2 acts through these signals. In humans, thickening of the IML (also called "junctional zone") is associated with reduced fertility, endometriosis and adenomyosis. Our data suggest that Foxl2 has a crucial role in PN uterine maturation and could help to understand sub-fertility predisposition in women.
authors: Évolution des Régulations Endocriniennes, CNRS UMR 7221, Muséum National d'Histoire Naturelle, Paris 75005, France and.
authors: Brice
authors: B
authors: Bellessort
authors: Évolution des Régulations Endocriniennes, CNRS UMR 7221, Muséum National d'Histoire Naturelle, Paris 75005, France and.
authors: Anne
authors: A
authors: Bachelot
authors: Évolution des Régulations Endocriniennes, CNRS UMR 7221, Muséum National d'Histoire Naturelle, Paris 75005, France and.
authors: Églantine
authors: É
authors: Heude
authors: Évolution des Régulations Endocriniennes, CNRS UMR 7221, Muséum National d'Histoire Naturelle, Paris 75005, France and.
authors: Gladys
authors: G
authors: Alfama
authors: Évolution des Régulations Endocriniennes, CNRS UMR 7221, Muséum National d'Histoire Naturelle, Paris 75005, France and.
authors: Anastasia
authors: A
authors: Fontaine
authors: Évolution des Régulations Endocriniennes, CNRS UMR 7221, Muséum National d'Histoire Naturelle, Paris 75005, France and.
authors: Marine
authors: M
authors: Le Cardinal
authors: Max-Delbrück Center for Molecular Medicine (MDC), Genetics of Metabolic and Reproductive Disorders, Robert-Rössle-Str. 10, Berlin 13125, Germany.
authors: Mathias
authors: M
authors: Treier
authors: Évolution des Régulations Endocriniennes, CNRS UMR 7221, Muséum National d'Histoire Naturelle, Paris 75005, France and glevi@mnhn.fr.
authors: Giovanni
authors: G
authors: Levi
mesh_terms: D000818:Animals; D005260:Female; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000502:physiology*; D056726:Genetic Association Studies; D007247:Infertility, Female / Q000235:genetics / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009130:Muscle, Smooth / Q000473:pathology; D009928:Organ Specificity; D014599:Uterus / Q000098:blood supply / Q000254:growth & development* / Q000473:pathology
chemical_list: D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; C498893:Foxl2 protein, mouse