title: Dlx5 and Dlx6 control uterine adenogenesis during post-natal maturation: possible consequences for endometriosis.
abstract: Dlx5 and Dlx6 are two closely associated homeobox genes which code for transcription factors involved in the control of steroidogenesis and reproduction. Inactivation of Dlx5/6 in the mouse results in a Leydig cell defect in the male and in ovarian insufficiency in the female. DLX5/6 are also strongly expressed by the human endometrium but their function in the uterus is unknown. The involvement of DLX5/6 in human uterine pathology is suggested by their strong downregulation in endometriotic lesions and upregulation in endometrioïd adenocarcinomas. We first show that Dlx5/6 expression begins in Müllerian ducts epithelia and persists then in the uterine luminal and glandular epithelia throughout post-natal maturation and in the adult. We then use a new mouse model in which Dlx5 and Dlx6 can be simultaneously inactivated in the endometrium using a Pgr(cre/+) allele. Post-natal inactivation of Dlx5/6 in the uterus results in sterility without any obvious ovarian involvement. The uteri of Pgr(cre/+); Dlx5/6(flox/flox) mice present very few uterine glands and numerous abnormally large and branched invaginations of the uterine lumen. In Dlx5/6 mutant uteri, the expression of genes involved in gland formation (Foxa2) and in epithelial remodelling during implantation (Msx1) is significantly reduced. Furthermore, we show that DLX5 is highly expressed in human endometrial glandular epithelium and that its expression is affected in endometriosis. We conclude that Dlx5 and Dlx6 expression determines uterine architecture and adenogenesis and is needed for implantation. Given their importance for female reproduction, DLX5 and DLX6 must be regarded as interesting targets for future clinical research.
authors.affiliation: Évolution des Régulations Endocriniennes, CNRS UMR 7221, Muséum Nationale d'Histoire Naturelle, Paris 75005, France.
authors.forename: Brice
authors.initials: B
authors.lastname: Bellessort
authors.affiliation: Évolution des Régulations Endocriniennes, CNRS UMR 7221, Muséum Nationale d'Histoire Naturelle, Paris 75005, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Le Cardinal
authors.affiliation: Évolution des Régulations Endocriniennes, CNRS UMR 7221, Muséum Nationale d'Histoire Naturelle, Paris 75005, France, AP-HP, Department of Endocrinology and Reproductive Medicine, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Pitié-Salpêtrière Hospital (Groupe Hospitalier Pitié-Salpêtrière), Université Pierre et Marie Curie, Site Pitié, 75013 Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Bachelot
authors.affiliation: Évolution des Régulations Endocriniennes, CNRS UMR 7221, Muséum Nationale d'Histoire Naturelle, Paris 75005, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Narboux-Nême
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum-University of Bologna, Bologna 40138, Italy, Interdepartmental Center 'L. Galvani', University of Bologna, Bologna 40126, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Garagnani
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum-University of Bologna, Bologna 40138, Italy, Interdepartmental Center 'L. Galvani', University of Bologna, Bologna 40126, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Pirazzini
authors.affiliation: Department of Experimental Medicine (DIMES) and, IRCCS AOU San Martino-IST, National Institute for Cancer Research, Genova, Italy and.
authors.forename: Ottavia
authors.initials: O
authors.lastname: Barbieri
authors.affiliation: Department of Experimental Medicine and Center of Excellence for Biomedical Research, Division of Anatomic Pathology, Department of Surgical Science and Integrated Diagnostics (DISC), University of Genoa, Genova, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Mastracci
authors.affiliation: Évolution des Régulations Endocriniennes, CNRS UMR 7221, Muséum Nationale d'Histoire Naturelle, Paris 75005, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Jonchere
authors.affiliation: Department of Régulations, Développement et Diversité Moléculaire, Muséum National d'Histoire Naturelle, Paris 75005, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Duvernois-Berthet
authors.affiliation: Évolution des Régulations Endocriniennes, CNRS UMR 7221, Muséum Nationale d'Histoire Naturelle, Paris 75005, France.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Fontaine
authors.affiliation: Évolution des Régulations Endocriniennes, CNRS UMR 7221, Muséum Nationale d'Histoire Naturelle, Paris 75005, France.
authors.forename: Gladys
authors.initials: G
authors.lastname: Alfama
authors.affiliation: Évolution des Régulations Endocriniennes, CNRS UMR 7221, Muséum Nationale d'Histoire Naturelle, Paris 75005, France, glevi@mnhn.fr.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Levi
mesh_terms: D000818:Animals; D010064:Embryo Implantation; D004715:Endometriosis / Q000235:genetics* / Q000378:metabolism; D004848:Epithelium / Q000254:growth & development; D005260:Female; D005786:Gene Expression Regulation; D005801:Genes, Homeobox; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D051379:Mice; D059467:Transcriptome; D014599:Uterus / Q000254:growth & development* / Q000378:metabolism
chemical_list: C501120:Dlx5 protein, mouse; C100597:Dlx6 protein, mouse; D018398:Homeodomain Proteins