TY - JOUR
T1 - FAF1, a Gene that Is Disrupted in Cleft Palate and Has Conserved Function in Zebrafish
AU - Ghassibe-Sabbagh, Michella
AU - Desmyter, Laurence
AU - Langenberg, Tobias
AU - Claes, Filip
AU - Boute, Odile
AU - Bayet, Benedicte
AU - Pellerin, Philippe
AU - Hermans, Karlien
AU - Backx, Liesbeth
AU - Mansilla, Maria Adela
AU - Imoehl, Sandra
AU - Nowak, Stefanie
AU - Ludwig, Kerstin U.
AU - Baluardo, Carlotta
AU - Ferrian, Melissa
AU - Mossey, Peter A.
AU - Noethen, Markus
AU - Dewerchin, Mieke
AU - Francois, Genevieve
AU - Revencu, Nicole
AU - Vanwijck, Romain
AU - Hecht, Jacqueline
AU - Mangold, Elisabeth
AU - Murray, Jeffrey
AU - Rubini, Michele
AU - Vermeesch, Joris R.
AU - Poirel, Helene A.
AU - Carmeliet, Peter
AU - Vikkula, Miikka
PY - 2011/2/11
Y1 - 2011/2/11
N2 - 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.
AB - 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.
KW - POPLITEAL PTERYGIUM SYNDROME
KW - PIERRE-ROBIN-SEQUENCE
KW - NEURAL CREST
KW - CHONDROCYTE DIFFERENTIATION
KW - MICE LACKING
KW - IRF6 GENE
KW - IKK-ALPHA
KW - WILD-TYPE
KW - KAPPA-B
KW - EXPRESSION
U2 - 10.1016/j.ajhg.2011.01.003
DO - 10.1016/j.ajhg.2011.01.003
M3 - Article
C2 - 21295280
SN - 0002-9297
VL - 88
SP - 150
EP - 161
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 2
ER -