title: Etiology of craniofacial malformations in mouse models of blepharophimosis, ptosis and epicanthus inversus syndrome.
abstract: Blepharophimosis, ptosis, epicanthus-inversus syndrome (BPES) is an autosomal dominant genetic disorder characterized by narrow palpebral fissures and eyelid levator muscle defects. BPES is often associated to premature ovarian insufficiency (BPES type I). FOXL2, a member of the forkhead transcription factor family, is the only gene known to be mutated in BPES. Foxl2 is essential for maintenance of ovarian identity, but the developmental origin of the facial malformations of BPES remains, so far, unexplained. In this study, we provide the first detailed account of the developmental processes leading to the craniofacial malformations associated to Foxl2. We show that, during development, Foxl2 is expressed both by Cranial Neural Crest Cells (CNCCs) and by Cranial Mesodermal Cells (CMCs), which give rise to skeletal (CNCCs and CMCs) and muscular (CMCs) components of the head. Using mice in which Foxl2 is selectively inactivated in either CNCCs or CMCs, we reveal that expression of Foxl2 in CNCCs is essential for the development of extraocular muscles. Indeed, inactivation of Foxl2 in CMCs has only minor effects on muscle development, whereas its inactivation in CNCCs provokes a severe hypoplasia of the levator palpabrae superioris and of the superior and inferior oblique muscles. We further show that Foxl2 deletion in either CNCCs or CMCs prevents eyelid closure and induces subtle skeletal developmental defects. Our results provide new insights in the complex developmental origin of human BPES and could help to understand the origin of other ocular anomalies associated to this syndrome.
authors.affiliation: Évolution des Régulations Endocriniennes, CNRS UMR 7221, Muséum National d'Histoire Naturelle, Paris 75005, France.
authors.forename: Églantine
authors.initials: É
authors.lastname: Heude
authors.affiliation: Évolution des Régulations Endocriniennes, CNRS UMR 7221, Muséum National 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 National d'Histoire Naturelle, Paris 75005, France.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Fontaine
authors.affiliation: Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Manatsu
authors.initials: M
authors.lastname: Hamazaki
authors.affiliation: Max-Delbrück Center for Molecular Medicine (MDC) - Genetics of Metabolic and Reproductive Disorders, Robert-Rössle-Str. 10, 13125 Berlin, Germany.
authors.forename: Anna-Corina
authors.initials: AC
authors.lastname: Treier
authors.affiliation: Max-Delbrück Center for Molecular Medicine (MDC) - Genetics of Metabolic and Reproductive Disorders, Robert-Rössle-Str. 10, 13125 Berlin, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Treier
authors.affiliation: Évolution des Régulations Endocriniennes, CNRS UMR 7221, Muséum National d'Histoire Naturelle, Paris 75005, France.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Levi
authors.affiliation: Évolution des Régulations Endocriniennes, CNRS UMR 7221, Muséum National d'Histoire Naturelle, Paris 75005, France, nnarboux-neme@mnhn.fr.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Narboux-Nême
mesh_terms: D000818:Animals; D016569:Blepharophimosis / Q000209:etiology*; D019465:Craniofacial Abnormalities / Q000209:etiology*; D005143:Eyelids / Q000002:abnormalities / Q000196:embryology*; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000235:genetics*; D017353:Gene Deletion; D015870:Gene Expression; D051379:Mice; D009801:Oculomotor Muscles / Q000002:abnormalities / Q000196:embryology*; D012868:Skin Abnormalities / Q000209:etiology*; D014564:Urogenital Abnormalities / Q000209:etiology*
chemical_list: D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; C498893:Foxl2 protein, mouse