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.
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.
Amy E
AE
Merrill
Elena G
EG
Bochukova
Sean M
SM
Brugger
Mamoru
M
Ishii
Daniela T
DT
Pilz
Steven A
SA
Wall
Karen M
KM
Lyons
Andrew O M
AO
Wilkie
Robert E
RE
Maxson
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