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Sf3b4-depleted Xenopus embryos: A model to study the pathogenesis of craniofacial defects in Nager syndrome.
Dev Biol 2016; 415(2):371-382DB

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+Show Affiliations

Department of Basic Science & Craniofacial Biology, College of Dentistry, New York University, New York, USA.Department of Basic Science & Craniofacial Biology, College of Dentistry, New York University, New York, USA.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.Department of Biological Sciences, College of Natural Sciences, Daegu University, Gyeongsan, Republic of Korea.Department of Basic Science & Craniofacial Biology, College of Dentistry, New York University, New York, USA. Electronic address: jsj4@nyu.edu.

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

26874011

Citation

Devotta, Arun, et al. "Sf3b4-depleted Xenopus Embryos: a Model to Study the Pathogenesis of Craniofacial Defects in Nager Syndrome." Developmental Biology, vol. 415, no. 2, 2016, pp. 371-382.
Devotta A, Juraver-Geslin H, Gonzalez JA, et al. Sf3b4-depleted Xenopus embryos: A model to study the pathogenesis of craniofacial defects in Nager syndrome. Dev Biol. 2016;415(2):371-382.
Devotta, A., Juraver-Geslin, H., Gonzalez, J. A., Hong, C. S., & Saint-Jeannet, J. P. (2016). Sf3b4-depleted Xenopus embryos: A model to study the pathogenesis of craniofacial defects in Nager syndrome. Developmental Biology, 415(2), pp. 371-382. doi:10.1016/j.ydbio.2016.02.010.
Devotta A, et al. Sf3b4-depleted Xenopus Embryos: a Model to Study the Pathogenesis of Craniofacial Defects in Nager Syndrome. Dev Biol. 2016 07 15;415(2):371-382. PubMed PMID: 26874011.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sf3b4-depleted Xenopus embryos: A model to study the pathogenesis of craniofacial defects in Nager syndrome. AU - Devotta,Arun, AU - Juraver-Geslin,Hugo, AU - Gonzalez,Jose Antonio, AU - Hong,Chang-Soo, AU - Saint-Jeannet,Jean-Pierre, Y1 - 2016/02/11/ PY - 2015/06/30/received PY - 2016/02/09/revised PY - 2016/02/10/accepted PY - 2016/2/14/entrez PY - 2016/2/14/pubmed PY - 2017/6/27/medline KW - BMP KW - Craniofacial KW - Nager syndrome KW - Neural crest KW - Sf3b4 KW - Splicing factor KW - Xenopus SP - 371 EP - 382 JF - Developmental biology JO - Dev. Biol. VL - 415 IS - 2 N2 - 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. SN - 1095-564X UR - https://www.unboundmedicine.com/medline/citation/26874011/Sf3b4_depleted_Xenopus_embryos:_A_model_to_study_the_pathogenesis_of_craniofacial_defects_in_Nager_syndrome_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0012-1606(16)30081-1 DB - PRIME DP - Unbound Medicine ER -