EIF4A3 deficient human iPSCs and mouse models demonstrate neural crest defects that underlie Richieri-Costa-Pereira syndrome.
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.
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA.
Emily E
EE
Miller
Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Institute of Biosciences, University of Sao Paulo, Sao Paulo, Brazil.
Gerson S
GS
Kobayashi
Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Institute of Biosciences, University of Sao Paulo, Sao Paulo, Brazil.
Camila M
CM
Musso
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA.
Miranda
M
Allen
Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Institute of Biosciences, University of Sao Paulo, Sao Paulo, Brazil.
Felipe A A
FAA
Ishiy
Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Institute of Biosciences, University of Sao Paulo, Sao Paulo, Brazil.
Luiz Carlos
LC
de Caires
Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Institute of Biosciences, University of Sao Paulo, Sao Paulo, Brazil.
Ernesto
E
Goulart
Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Institute of Biosciences, University of Sao Paulo, Sao Paulo, Brazil.
Karina
K
Griesi-Oliveira
Department of Clinical Genetics, Hospital for Rehabilitation of Craniofacial Anomalies (HRCA), University of São Paulo, Bauru, Brazil.
Roseli M
RM
Zechi-Ceide
Department of Clinical Genetics, Hospital for Rehabilitation of Craniofacial Anomalies (HRCA), University of São Paulo, Bauru, Brazil.
Antonio
A
Richieri-Costa
Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Institute of Biosciences, University of Sao Paulo, Sao Paulo, Brazil.
Debora R
DR
Bertola
Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Institute of Biosciences, University of Sao Paulo, Sao Paulo, Brazil.
Maria Rita
MR
Passos-Bueno
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.
Debra L
DL
Silver
D000818:Animals; D001842:Bone and Bones / Q000378:metabolism; D001934:Branchial Region / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002465:Cell Movement; D020219:Chondrogenesis / Q000235:genetics; D003025:Clubfoot / Q000235:genetics* / Q000378:metabolism; D019465:Craniofacial Abnormalities / Q000235:genetics / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D039601:Eukaryotic Initiation Factor-4A / Q000235:genetics* / Q000378:metabolism*; D006228:Hand Deformities, Congenital / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D051379:Mice; D009432:Neural Crest / Q000254:growth & development / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics; D010855:Pierre Robin Syndrome / Q000235:genetics* / Q000378:metabolism
D039601:Eukaryotic Initiation Factor-4A; C403493:EIF4A3 protein, human; D053487:DEAD-box RNA Helicases