Portal de Periódicos da CAPES

FAF1, a Gene that Is Disrupted in Cleft Palate and Has Conserved Function in Zebrafish

2011; Elsevier BV; Volume: 88; Issue: 2 Linguagem: Inglês

10.1016/j.ajhg.2011.01.003

1537-6605

Michella Ghassibe‐Sabbagh, Laurence Desmyter, Tobias Langenberg, Filip Claes, Odile Boute, Bénédicte Bayet, P. Pellerin, Karlien Hermans, Liesbeth Backx, M. Adela Mansilla, Sandra R. Imoehl, Stefanie Nowak, Kerstin U. Ludwig, Carlotta Baluardo, Melissa Ferrian, Peter Mossey, Markus M. Nöethen, Mieke Dewerchin, Geneviève François, Nicole Revençu, R Vanwijck, Jacqueline T. Hecht, Elisabeth Mangold, Jeffrey C. Murray, Michele Rubini, Joris Vermeesch, Hélène A. Poirel, Peter Carmeliet, Miikka Vikkula,

Congenital Anomalies and Fetal Surgery

Cranial neural crest (CNC) is a multipotent migratory cell population that gives rise to most of the craniofacial bones. An intricate network mediates CNC formation, epithelial-mesenchymal transition, migration along distinct paths, and differentiation. Errors in these processes lead to craniofacial abnormalities, including cleft lip and palate. Clefts are the most common congenital craniofacial defects. Patients have complications with feeding, speech, hearing, and dental and psychological development. Affected by both genetic predisposition and environmental factors, the complex etiology of clefts remains largely unknown. Here we show that Fas-associated factor-1 (FAF1) is disrupted and that its expression is decreased in a Pierre Robin family with an inherited translocation. Furthermore, the locus is strongly associated with cleft palate and shows an increased relative risk. Expression studies show that faf1 is highly expressed in zebrafish cartilages during embryogenesis. Knockdown of zebrafish faf1 leads to pharyngeal cartilage defects and jaw abnormality as a result of a failure of CNC to differentiate into and express cartilage-specific markers, such as sox9a and col2a1. Administration of faf1 mRNA rescues this phenotype. Our findings therefore identify FAF1 as a regulator of CNC differentiation and show that it predisposes humans to cleft palate and is necessary for lower jaw development in zebrafish. Cranial neural crest (CNC) is a multipotent migratory cell population that gives rise to most of the craniofacial bones. An intricate network mediates CNC formation, epithelial-mesenchymal transition, migration along distinct paths, and differentiation. Errors in these processes lead to craniofacial abnormalities, including cleft lip and palate. Clefts are the most common congenital craniofacial defects. Patients have complications with feeding, speech, hearing, and dental and psychological development. Affected by both genetic predisposition and environmental factors, the complex etiology of clefts remains largely unknown. Here we show that Fas-associated factor-1 (FAF1) is disrupted and that its expression is decreased in a Pierre Robin family with an inherited translocation. Furthermore, the locus is strongly associated with cleft palate and shows an increased relative risk. Expression studies show that faf1 is highly expressed in zebrafish cartilages during embryogenesis. Knockdown of zebrafish faf1 leads to pharyngeal cartilage defects and jaw abnormality as a result of a failure of CNC to differentiate into and express cartilage-specific markers, such as sox9a and col2a1. Administration of faf1 mRNA rescues this phenotype. Our findings therefore identify FAF1 as a regulator of CNC differentiation and show that it predisposes humans to cleft palate and is necessary for lower jaw development in zebrafish.