Cell mixing at a neural crest-mesoderm boundary and deficient ephrin-Eph signaling in the pathogenesis of craniosynostosis.
Boundaries between cellular compartments often serve as signaling interfaces during embryogenesis. The coronal suture is a major growth center of the skull vault and develops at a boundary between cells derived from neural crest and mesodermal origin, forming the frontal and parietal bones, respectively. Premature fusion of these bones, termed coronal synostosis, is a common human developmental anomaly. Known causes of coronal synostosis include haploinsufficiency of TWIST1 and a gain of function mutation in MSX2. In Twist1(+/-) mice with coronal synostosis, we found that the frontal-parietal boundary is defective. Specifically, neural crest cells invade the undifferentiated mesoderm of the Twist1(+/-) mutant coronal suture. This boundary defect is accompanied by an expansion in Msx2 expression and reduction in ephrin-A4 distribution. Reduced dosage of Msx2 in the Twist1 mutant background restores the expression of ephrin-A4, rescues the suture boundary and inhibits craniosynostosis. Underlining the importance of ephrin-A4, we identified heterozygous mutations in the human orthologue, EFNA4, in three of 81 patients with non-syndromic coronal synostosis. This provides genetic evidence that Twist1, Msx2 and Efna4 function together in boundary formation and the pathogenesis of coronal synostosis.
Merrill
Amy E
AE
Department of Biochemistry and Molecular Biology, Norris Cancer Hospital, University of Southern Califoirnia Keck School of Medicine, 1441 Eastlake Avenue, Los Angeles, CA 90089-0176, USA.
Bochukova
Elena G
EG
Brugger
Sean M
SM
Ishii
Mamoru
M
Pilz
Daniela T
DT
Wall
Steven A
SA
Lyons
Karen M
KM
Wilkie
Andrew O M
AO
Maxson
Robert E
RE
D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003393:Cranial Sutures / Q000378:metabolism*; D003398:Craniosynostoses / Q000378:metabolism* / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D036383:Ephrin-A2 / Q000235:genetics / Q000378:metabolism; D036385:Ephrin-A4 / Q000235:genetics / Q000378:metabolism; D036342:Ephrins / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D009432:Neural Crest / Q000166:cytology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D036081:Receptors, Eph Family / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; D036383:Ephrin-A2; D036385:Ephrin-A4; D036342:Ephrins; D018398:Homeodomain Proteins; C084119:MSX2 protein; D009687:Nuclear Proteins; D051879:Twist-Related Protein 1; C067250:Twist1 protein, mouse; D036081:Receptors, Eph Family