Determining the role of Growth Differentiation Factor-6 (Gdf6) in the development of the coronal suture

Abstract

HUMAN GENETICS

DETERMINING THE ROLE OF GROWTH DIFFERENTIATION FACTOR-6 (GDF6) IN THE DEVELOPMENT OF THE CORONAL SUTURE

DAWN ELIZABETH CLENDENNING

Dissertation under the direction of Professor Douglas P. Mortlock Growth differentiation factor-6 (Gdf6) is a member of the Bone Morphogenetic Protein (BMP) family of secreted signaling proteins. The Gdf6 mutant mouse presents with fusions in the bones of the wrist and ankle, hypoplasia of the thyroid cartilage, abnormalities of the bones of the middle ear, and craniosynostosis of the coronal suture. Craniosynostosis is the premature fusion of one or more of the cranial sutures, the joints that separate the flat bones of the skull. The primary objective of this work was to determine the developmental timing of the coronal suture defect, when and where Gdf6 is expressed during cranial development, what mechanism leads to fusion of the coronal suture, and how Gdf6 interacts with other members of the BMP family in coronal suture development. We found that Gdf6 is expressed in the rudiment of the frontal bone early in suture development. Loss of Gdf6 leads to the osteogenic differentiation of the coronal suture mesenchyme, which must remain undifferentiated to remain a site for cranial growth. Furthermore, Gdf6 interacts with fellow BMP family member Bmp4 not only in the development of the coronal suture, but in multiple skeletal elements. Additionally, we found that the BMP antagonist Noggin does not play an important role in embryonic suture development. The findings of this project not only further the the study of craniosynostosis but also broadens the knowledge of the roles of BMPs.