title: Sf3b4-depleted Xenopus embryos: A model to study the pathogenesis of craniofacial defects in Nager syndrome.
abstract: Mandibulofacial dysostosis (MFD) is a human developmental disorder characterized by defects of the facial bones. It is the second most frequent craniofacial malformation after cleft lip and palate. Nager syndrome combines many features of MFD with a variety of limb defects. Mutations in SF3B4 (splicing factor 3b, subunit 4) gene, which encodes a component of the pre-mRNA spliceosomal complex, were recently identified as a cause of Nager syndrome, accounting for 60% of affected individuals. Nothing is known about the cellular pathogenesis underlying Nager type MFD. Here we describe the first animal model for Nager syndrome, generated by knocking down Sf3b4 function in Xenopus laevis embryos, using morpholino antisense oligonucleotides. Our results indicate that Sf3b4-depleted embryos show reduced expression of the neural crest genes sox10, snail2 and twist at the neural plate border, associated with a broadening of the neural plate. This phenotype can be rescued by injection of wild-type human SF3B4 mRNA but not by mRNAs carrying mutations that cause Nager syndrome. At the tailbud stage, morphant embryos had decreased sox10 and tfap2a expression in the pharyngeal arches, indicative of a reduced number of neural crest cells. Later in development, Sf3b4-depleted tadpoles exhibited hypoplasia of neural crest-derived craniofacial cartilages, phenocopying aspects of the craniofacial skeletal defects seen in Nager syndrome patients. With this animal model we are now poised to gain important insights into the etiology and pathogenesis of Nager type MFD, and to identify the molecular targets of Sf3b4.
authors.affiliation: Department of Basic Science & Craniofacial Biology, College of Dentistry, New York University, New York, USA.
authors.forename: Arun
authors.initials: A
authors.lastname: Devotta
authors.affiliation: Department of Basic Science & Craniofacial Biology, College of Dentistry, New York University, New York, USA.
authors.forename: Hugo
authors.initials: H
authors.lastname: Juraver-Geslin
authors.affiliation: Department of Basic Science & Craniofacial Biology, College of Dentistry, New York University, New York, USA; Master Program in Biology, New York University, New York, USA.
authors.forename: Jose Antonio
authors.initials: JA
authors.lastname: Gonzalez
authors.affiliation: Department of Biological Sciences, College of Natural Sciences, Daegu University, Gyeongsan, Republic of Korea.
authors.forename: Chang-Soo
authors.initials: CS
authors.lastname: Hong
authors.affiliation: Department of Basic Science & Craniofacial Biology, College of Dentistry, New York University, New York, USA. Electronic address: jsj4@nyu.edu.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Saint-Jeannet
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001934:Branchial Region / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D002356:Cartilage / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D018389:Codon, Nonsense; D004195:Disease Models, Animal; D016368:Frameshift Mutation; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D055785:Gene Knockdown Techniques; D005816:Genetic Complementation Test; D006801:Humans; D008342:Mandibulofacial Dysostosis / Q000196:embryology / Q000235:genetics* / Q000503:physiopathology; D008445:Maxillofacial Development / Q000235:genetics*; D008969:Molecular Sequence Data; D060172:Morpholinos / Q000494:pharmacology; D009432:Neural Crest / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D054258:Neural Plate / Q000196:embryology / Q000473:pathology; D010641:Phenotype; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing / Q000235:genetics; D000072260:RNA Splicing Factors / Q000235:genetics*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012886:Skull / Q000002:abnormalities / Q000196:embryology / Q000254:growth & development; D029867:Xenopus Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D014982:Xenopus laevis / Q000196:embryology / Q000235:genetics* / Q000254:growth & development
chemical_list: D018389:Codon, Nonsense; D060172:Morpholinos; D012322:RNA Precursors; D000072260:RNA Splicing Factors; C486347:SF3B4 protein, human; C000620752:Sf3b4 protein, Xenopus; D029867:Xenopus Proteins
keywords: BMP; Craniofacial; Nager syndrome; Neural crest; Sf3b4; Splicing factor; Xenopus