Craniosynostosis is a debilitating condition characterized by premature cranial suture fusion, resulting in abnormal skull shape, blindness and mental retardation. The prevalence of craniosynostosis is at 1 in 2,500 live births, which is one of the highest incidences of congenital malformation of 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 demonstrated that craniosynostosis is associated with mutations in FGF signaling components, Twist, Msx2 and Efnb1, however, genetic causes of majority (70%) of craniosynostosis are still unknown. Involvement of BMP signaling to craniosynostosis is recently proposed. We developed a new mouse model for craniosynostosis characterized by premature fusion of a metopic suture by a gain-of-function mutation in a BMP signaling component. This model is unique and important because 1) upregulation of FGF signaling is observed, 2) ectopic cartilage is formed at the site of fusion prior to the fusion, and 3) the phenotype is rescued in heterozygous null background of BMPRIA, indicating that the precise control of BMP signaling is critical to prevent craniosynostosis. We will use this model to investigate molecular mechanisms by which leads to pathogenesis. Our study will further define molecular pathways directly involves in pathogenesis of premature fusion of cranial sutures leading to craniosynostosis, and will therefore provide better insights for potential molecular targets for therapeutic treatment of human cases.

Public Health Relevance

In this proposal, we will define the molecular mechanism by which gain-of-function mutations in BMP signaling components lead to craniosynostosis. Genetic causes of majority (70%) of craniosynostosis are still unknown. Involvement of BMP signaling to craniosynostosis is recently proposed. We developed a new mouse model for craniosynostosis characterized by premature fusion of a metopic suture by a gain-of- function mutation in a BMP signaling component. We will use this model to investigate molecular mechanisms by which leads to pathogenesis. Our study will further define molecular pathways directly involves in pathogenesis of premature fusion of cranial sutures leading to craniosynostosis, and will therefore provide better insights for potential molecular targets for therapeutic treatment of human cases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE020843-03
Application #
8230522
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Lumelsky, Nadya L
Project Start
2010-05-01
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
3
Fiscal Year
2012
Total Cost
$382,388
Indirect Cost
$134,888
Name
University of Michigan Ann Arbor
Department
None
Type
Schools of Dentistry
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Komatsu, Yoshihiro; Kishigami, Satoshi; Mishina, Yuji (2014) In situ hybridization methods for mouse whole mounts and tissue sections with and without additional *-galactosidase staining. Methods Mol Biol 1092:1-15
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