| First Author | Merrill AE | Year | 2006 |
| Journal | Hum Mol Genet | Volume | 15 |
| Issue | 8 | Pages | 1319-28 |
| PubMed ID | 16540516 | Mgi Jnum | J:144134 |
| Mgi Id | MGI:3830156 | Doi | 10.1093/hmg/ddl052 |
| Citation | Merrill AE, et al. (2006) Cell mixing at a neural crest-mesoderm boundary and deficient ephrin-Eph signaling in the pathogenesis of craniosynostosis. Hum Mol Genet 15(8):1319-28 |
| abstractText | 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. |
