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Human Molecular Genetics Advance Access originally published online on March 15, 2006
Human Molecular Genetics 2006 15(8):1319-1328; doi:10.1093/hmg/ddl052
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© The Author 2006. Published by Oxford University Press. All rights reserved.
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact: journals.permissions@oxfordjournals.org

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

Amy E. Merrill1,{dagger}, Elena G. Bochukova2,{dagger}, Sean M. Brugger3, Mamoru Ishii1, Daniela T. Pilz4, Steven A. Wall5, Karen M. Lyons3, Andrew O.M. Wilkie2,* and Robert E. Maxson, Jr1,*

1Department of Biochemistry and Molecular Biology, Norris Cancer Hospital, University of Southern California Keck School of Medicine, 1441 Eastlake Avenue, Los Angeles, CA 90089-9176, USA, 2Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK, 3Departments of Orthopaedic Surgery and Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA 90095, USA, 4Institute of Medical Genetics, University Hospital of Wales, Cardiff CF14 4XW, UK and 5Craniofacial Unit, Department of Plastic Surgery, Radcliffe Infirmary, Oxford OX2 6HE, UK

* To whom correspondence should be addressed. Tel: +1 3238650633; Fax: +1 3238650098; Email: maxson{at}hsc.usc.edu (R.E.M.) or Tel: +44 1865222619; Fax: +44 1865222500; Email: awilkie{at}hammer.imm.ox.ac.uk (A.O.M.W.)

Received January 14, 2006; Accepted March 7, 2006

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.

{dagger}The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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