EIF4A3 deficient human iPSCs and mouse models demonstrate neural crest defects that underlie Richieri-Costa-Pereira syndrome.

Autor:	Miller EE; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA., Kobayashi GS; Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Institute of Biosciences, University of Sao Paulo, Sao Paulo, Brazil., Musso CM; Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Institute of Biosciences, University of Sao Paulo, Sao Paulo, Brazil., Allen M; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA., Ishiy FAA; Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Institute of Biosciences, University of Sao Paulo, Sao Paulo, Brazil., de Caires LC Jr; Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Institute of Biosciences, University of Sao Paulo, Sao Paulo, Brazil., Goulart E; Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Institute of Biosciences, University of Sao Paulo, Sao Paulo, Brazil., Griesi-Oliveira K; Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Institute of Biosciences, University of Sao Paulo, Sao Paulo, Brazil., Zechi-Ceide RM; Department of Clinical Genetics, Hospital for Rehabilitation of Craniofacial Anomalies (HRCA), University of São Paulo, Bauru, Brazil., Richieri-Costa A; Department of Clinical Genetics, Hospital for Rehabilitation of Craniofacial Anomalies (HRCA), University of São Paulo, Bauru, Brazil., Bertola DR; Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Institute of Biosciences, University of Sao Paulo, Sao Paulo, Brazil., Passos-Bueno MR; Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Institute of Biosciences, University of Sao Paulo, Sao Paulo, Brazil., Silver DL; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA.; Department of Neurobiology.; Department of Cell Biology.; Duke Institute for Brain Sciences, Duke University Medical Center, Durham, NC, USA.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2017 Jun 15; Vol. 26 (12), pp. 2177-2191.
DOI:	10.1093/hmg/ddx078
Abstrakt:	Biallelic loss-of-function mutations in the RNA-binding protein EIF4A3 cause Richieri-Costa-Pereira syndrome (RCPS), an autosomal recessive condition mainly characterized by craniofacial and limb malformations. However, the pathogenic cellular mechanisms responsible for this syndrome are entirely unknown. Here, we used two complementary approaches, patient-derived induced pluripotent stem cells (iPSCs) and conditional Eif4a3 mouse models, to demonstrate that defective neural crest cell (NCC) development explains RCPS craniofacial abnormalities. RCPS iNCCs have decreased migratory capacity, a distinct phenotype relative to other craniofacial disorders. Eif4a3 haploinsufficient embryos presented altered mandibular process fusion and micrognathia, thus recapitulating the most penetrant phenotypes of the syndrome. These defects were evident in either ubiquitous or NCC-specific Eif4a3 haploinsufficient animals, demonstrating an autonomous requirement of Eif4a3 in NCCs. Notably, RCPS NCC-derived mesenchymal stem-like cells (nMSCs) showed premature bone differentiation, a phenotype paralleled by premature clavicle ossification in Eif4a3 haploinsufficient embryos. Likewise, nMSCs presented compromised in vitro chondrogenesis, and Meckel's cartilage was underdeveloped in vivo. These findings indicate novel and essential requirements of EIF4A3 for NCC migration and osteochondrogenic differentiation during craniofacial development. Altogether, complementary use of iPSCs and mouse models pinpoint unique cellular mechanisms by which EIF4A3 mutation causes RCPS, and provide a paradigm to study craniofacial disorders. (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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