Cell mixing at a neural crest-mesoderm boundary and deficient ephrin-Eph signaling in the pathogenesis of craniosynostosis.

Journal article

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.

Authors: Merrill, A; Bochukova, E; Brugger, S; Ishii, M; Pilz, D

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Oxford University Press
• Journal: Human molecular genetics
• Volume: 15
• Issue: 8
• Pages: 1319-1328
• Publication date: 2006-04-01
• DOI: 10.1093/hmg/ddl052
• EISSN: 1460-2083
• ISSN: 0964-6906
• Language: English
• Keywords: Immunohistochemistry; Nuclear Proteins; Mutation; Tumor Cells, Cultured; Homeodomain Proteins; Molecular Sequence Data; Embryo, Mammalian; DNA-Binding Proteins; Neural Crest; Cranial Sutures; Animals; Ephrin-A2; Mice, Transgenic; Craniosynostoses; Heterozygote; Gene Expression Regulation, Developmental; Phenotype; Mice; Humans; Cercopithecus aethiops; Receptors, Eph Family; Mice, Inbred C57BL; Ephrins; Base Sequence; COS Cells; Cells, Cultured; Ephrin-A4; Twist Transcription Factor; Signal Transduction; Mesoderm