Genetic analysis of bone morphogenetic proteins during skeletal development, pattern formation, and tissue signaling

Bone morphogenetic proteins (BMPs) are multifunctional secreted signaling molecules necessary for normal skeletal development. Previous studies have demonstrated that BMPs are necessary and sufficient for the condensation of mesenchyme cells into skeletal element precursors. This is a necessary first step in skeletal development. In addition to functioning during mesenchymal condensations, recent work on a novel member of the BMP family, Gdf5 , has demonstrated a possible role for BMPs in joint development. Gdf5 is expressed in nearly all developing limb joints and Gdf5 mutants display joint abnormalities. Gdf5 is a member of a distinct subgroup within the BMP family that includes two other members, Gdf6 and Gdf7.; In my dissertation work, I examine the expression pattern and function of the Gdf6 and Gdf7 genes during skeletal and soft tissue development. I have generated mutants in these two genes using homologous recombination in embryonic stem cells. I show that the Gdf6 and Gdf7 genes are also expressed in developing joints, but the expression is seen in specific subsets of limb joints. I also observe expression of Gdf7 in the mesenchyme of the developing male reproductive system, suggesting a role for this subgroup of BMPs during soft tissue development.; Examination of the phenotypes of the Gdf6 and Gdf7 mutants demonstrates a role for these genes in both soft tissue and skeletal development. The Gdf6 mutant shows fusions of specific joints at locations where expression is concentrated. Most notably, Gdf6 mutants lack a specific skull suture joint, the coronal suture, causing the mutant mice to have craniosynostosis.; Craniosynostosis is a common human disease and this work identifies a candidate gene to examine in human craniosynostosis pedigrees and provides an animal model for this disease. The Gdf7 mutant mice display abnormalities in the normal growth and development of seminal vesicle epithelium, demonstrating a role for this gene in the normal epithelial-mesenchymal interactions necessary for growth and development of this structure. This work provides further insight into the role of this subgroup of BMPs demonstrating that they are multifunctional regulators of both skeletal and soft tissue development.