Identification and Validation of Gene Expression Profile in Facial Dysmorphology of Craniosynostosis Crouzon Syndrome

Craniosynostosis causes malformations of the skull that are characterized by premature suture closure, as well as brain and facial malformations. Recent work in mice, and our preliminary data, suggest that the malformations in the brain and face are a primary consequence of mutations in craniosynostosis patients. Gain‐of‐function mutations in Fibroblast growth factor receptors (FgfR1‐3) account for ~25% of all craniosynostosis syndromes. To investigate mechanisms underlying facial malformations due to mutations in FgfR2, we infected chick embryos with a retrovirus encoding FgfR2C278F that causes craniosynostosis in humans. Compared to normal embryos, infected embryos have widened‐faces and midfacial dysplasia that resemble the defects seen in craniosynostosis. These alterations were associated with a significant reduction in cell proliferation. Further, changes in gene expression detected by microarray analysis may contribute to the phenotypic and cellular outcomes. In particular, Lin28, an inhibitor of Let7 microRNA maturation, was upregulated and sustained for longer periods. Crispld2, a nonsyndromic cleft lip palate related gene, is downregulated. Dlg1, a gene regulating cell polarity, is upregulated and its interacting protein Scribble shows increase membrane‐localization in neural crest cell in FgfR2C278F embryos compared to normal embryos. Grant Funding Source: NIH