The long term goals of this project are to generate and characterize mouse models of human craniofacial disease syndromes, and to understand the genetic and biochemical pathways underlying these disease syndromes. Craniosynostosis, the premature fusion of the calvarial bones of the skull, is a significant medical problem, occurring in 1 in 3000 live births. The abnormal skull growth associated with craniosynostosis may result in raised intracranial pressure, impaired cerebral blood flow, airway obstruction, impaired vision and hearing learning difficulties and adverse psychological effects. In this proposal, we will study a mouse model for Saethre-Chotzen Syndrome, one of the most common autosomal dominant disorders of craniosynostosis in humans. Haploinsufficiency for the human TWIST gene, which encodes a bHLH-type transcription factor, has been demonstrated to be one of the major causes of Saethre-Chotzen Syndrome. Other familial cases of Saethre-Chotzen Syndrome are caused by mutations in some of the genes encoding fibroblast growth factor receptors (FGR2 and FGR3). A null mutation in the mouse Twist gene results in early embryonic death in homozygotes, and in heterozygotes results in partially penetrant skeletal defects that replicate certain features of Saethre-Chotzen syndrome. The human TWIST gene is a homolog of the Twist gene of Drosophila. Genetic evidence in Drosophila has demonstrated that mutations in the Twist gene interact with mutations in another transcription factor encoded by the Snail gene. We have constructed targeted mutations in two mouse homologs of Snail (termed Sna and Slug). We will test the hypothesis that, as in Drosophila, genes of the Snail and Twist family both function in the same genetic pathway in mice.
The specific aims of this proposal are to: 1. Further characterize Twist mutant embryos by testing fro altered expression of the Snail family genes Sna and Slug. Also examine whether expression of other genes responsible for inherited craniosynostosis syndromes (the fibroblast growth factor receptors and the Msx genes) are altered in Twist mutant embryos. 2. Test the hypothesis that, as in Drosophila, genes of the Twist and Snail families will function in the same genetic pathway by generating and analyzing Sna/Twist double mutants. 3. Generate and analyze double mutants with the mother mouse Snail family gene Slug (Slug/Twist double mutants).

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Comprehensive Center (P60)
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Johns Hopkins University
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