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XB-ART-51882
Dev Biol July 15, 2016; 415 (2): 371-382.

Sf3b4-depleted Xenopus embryos: A model to study the pathogenesis of craniofacial defects in Nager syndrome.

Devotta A , Juraver-Geslin H , Gonzalez JA , Hong CS , Saint-Jeannet JP .


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.

PubMed ID: 26874011
PMC ID: PMC4914463
Article link: Dev Biol
Grant support: [+]
Genes referenced: h3-3a krt12.4 msx1 pax3 sf3b4 smad1 snai2 sox10 sox2 sox9 tfap2a twist1
GO keywords: RNA splicing [+]
Antibodies: Sf3b4 Ab1 Smad1 Ab12 Tuba4b Ab2
Morpholinos: sf3b4 MO1 sf3b4 MO2

Disease Ontology terms: Nager acrofacial dysostosis
OMIMs: ACROFACIAL DYSOSTOSIS 1, NAGER TYPE; AFD1

Article Images: [+] show captions
References:
, 1996, Pubmed [+]


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