title: FAF1, a gene that is disrupted in cleft palate and has conserved function in zebrafish.
abstract: 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.
authors.affiliation: Laboratory of Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium.
authors.forename: Michella
authors.initials: M
authors.lastname: Ghassibe-Sabbagh
authors.forename: Laurence
authors.initials: L
authors.lastname: Desmyter
authors.forename: Tobias
authors.initials: T
authors.lastname: Langenberg
authors.forename: Filip
authors.initials: F
authors.lastname: Claes
authors.forename: Odile
authors.initials: O
authors.lastname: Boute
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Bayet
authors.forename: Philippe
authors.initials: P
authors.lastname: Pellerin
authors.forename: Karlien
authors.initials: K
authors.lastname: Hermans
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Backx
authors.forename: Maria Adela
authors.initials: MA
authors.lastname: Mansilla
authors.forename: Sandra
authors.initials: S
authors.lastname: Imoehl
authors.forename: Stefanie
authors.initials: S
authors.lastname: Nowak
authors.forename: Kerstin U
authors.initials: KU
authors.lastname: Ludwig
authors.forename: Carlotta
authors.initials: C
authors.lastname: Baluardo
authors.forename: Melissa
authors.initials: M
authors.lastname: Ferrian
authors.forename: Peter A
authors.initials: PA
authors.lastname: Mossey
authors.forename: Markus
authors.initials: M
authors.lastname: Noethen
authors.forename: Mieke
authors.initials: M
authors.lastname: Dewerchin
authors.forename: Geneviève
authors.initials: G
authors.lastname: François
authors.forename: Nicole
authors.initials: N
authors.lastname: Revencu
authors.forename: Romain
authors.initials: R
authors.lastname: Vanwijck
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Hecht
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mangold
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Murray
authors.forename: Michele
authors.initials: M
authors.lastname: Rubini
authors.forename: Joris R
authors.initials: JR
authors.lastname: Vermeesch
authors.forename: Hélène A
authors.initials: HA
authors.lastname: Poirel
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Miikka
authors.initials: M
authors.lastname: Vikkula
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D030801:Animals, Genetically Modified; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D002356:Cartilage / Q000378:metabolism; D002454:Cell Differentiation; D002972:Cleft Palate / Q000209:etiology* / Q000473:pathology; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D009154:Mutation / Q000235:genetics*; D009432:Neural Crest / Q000378:metabolism* / Q000473:pathology; D010375:Pedigree; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development; D029961:Zebrafish Proteins / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C490780:FAF1 protein, human; D012333:RNA, Messenger; D029961:Zebrafish Proteins