Srf in MAPK-dependent cranial suture development

Case Western Reserve University, Cleveland OH

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Abstract

DESCRIPTION (provided by applicant): Activating mutations in FGFR2 cause craniosynostosis syndromes such as Apert and Crouzon syndromes. Recent genetic evidence has also indicated that the ERK MAPK pathway and immediate early genes play critical roles in the regulation of bone formation. Therefore, we hypothesize that Srf, a transcription factor that regulates expression of many immediate early genes, plays critical roles in the FGF and MAPK regulation of bone formation and cranial suture development. We will test the hypothesis by pursuing the following Specific Aims. The first Specific Aim is to identify the roles of Srf in MAPK-dependent bone formation. The second Specific Aim is to identify the roles of Srf in mediating FGF signaling in osteoblasts. These experiments will greatly advance our knowledge about the roles of FGF and the ERK MAPK pathway in regulating bone formation and cranial suture closure. The elucidation of the molecular mechanisms will eventually lead to the development of new therapies to control bone formation in various skeletal disorders including craniosynostosis. PUBLIC HEALTH RELEVANCE: FGF signaling has been implicated in craniosynostosis syndromes. In addition, mutations in the molecules in the ERK MAPK pathway have been identified in a number of skeletal syndromes. This study identifies novel regulatory mechanisms of bone formation by FGF and the ERK MAPK pathway. The identification of the regulatory mechanisms will provide much needed information for controlling bone formation in various skeletal disorders such as craniosynostosis.