Craniosynostosis is a debilitating condition characterized by premature cranial suture fusion resulting in abnormal skull shape. Deafness, blindness, and mental retardation often accompany this finding and an extensive series of surgeries is commonly required. The estimated prevalence of craniosynostosis is 1:2,500 live births making it one of the most prevalent congenital malformations affecting the skeletal system. The long- term goal of the proposed studies is to define the molecular mechanism by which gain-of-function mutations in BMP signaling components lead to craniosynostosis. Recent studies show craniosynostosis is associated with mutations in several genes; however, genetic causes of majority (70%) of craniosynostosis are still unknown. Involvement of BMP signaling in craniosynostosis has been recently proposed. We developed a new mouse model for craniosynostosis characterized by premature fusion of the metopic suture via gain-of-function mutation in a BMP signaling component. This model is unique and important due to: 1) upregulation of p53- induced apoptosis is observed, 2) ectopic cartilage is formed at the site of fusion prior to premature fusion, and 3) the phenotype is rescued in the heterozygous null background of Bmpr1a indicating precise control of BMP signaling is critical for preventing craniosynostosis. Together these finding suggest novel mechanisms for premature suture fusion. We will identify critical downstream molecules and signaling pathways for craniosynostosis and establish treatment methods using chemical inhibitors for specific signaling pathways coupled with our newly developed gene silencing method. Our study will further define molecular pathways directly involved in the pathogenesis of premature fusion of cranial sutures leading to craniosynostosis and will provide better insights for potential molecular targets during therapeutic treatment of human cases.

Public Health Relevance

Through the aims outlined in this proposal we will define the molecular and cellular mechanism by which gain-of-function mutations in the BMP signaling pathway lead to craniosynostosis resulting in craniofacial deformity. A majority of genetic causes (70%) of craniosynostosis are still unknown; however, BMP signaling has been implicated as a player in some forms of craniosynostosis. We will use newly developed mouse models for craniosynostosis. These mice exhibit premature fusion of cranial sutures recapitulating human disease. Our study will determine the extent increased cell death and aberrant cell fate specification in the cranial neural crest stem cell population deplete the sutur mesenchyme stem cell population resulting in premature fusion of cranial sutures. Results from our study will therefore provide better potential molecular targets for therapeutic treatment of human cases.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Skeletal Biology Structure and Regeneration Study Section (SBSR)
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Lumelsky, Nadya L
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University of Michigan Ann Arbor
Schools of Dentistry/Oral Hygn
Ann Arbor
United States
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