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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.

Etiology of craniofacial malformations in mouse models of blepharophimosis, ptosis and epicanthus inversus syndrome