GENETIC ANALYSIS OF BONE MORPHOGENETIC PROTEINS

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The long term goal of this research is to define the molecular mechanisms that control the growth and patterning of skeletal tissue. This is a general problem in the development of higher animals, and is of particular relevance to the diagnosis and treatment of human skeletal diseases and bone fractures. The studies are particularly directed to understanding the role of bone morphogenetic proteins (BMPs) in normal development. BMPs were originally isolated based on their ability to induce cartilage and bone formation when implanted under the skin of animals. Combinations of BMPs and a carrier matrix are sufficient to induce a complex cascade of chemotactic and differentiation events that ultimately results in the formation of a marrow filled bony ossicle at ectopic body sites. The presence of these proteins in mature bones, and their ability to stimulate new bone formation, suggests that they may be the natural mediators of bone growth and modeling during embryonic development and repair of bone fractures. Cloning studies have shown that most BMPs are members of a family of secreted signaling molecules that have structural homology to transforming growth factor beta. The BMPs are strikingly conserved in evolution, with close relatives present in organisms such as the fruit fly Drosophila. BMP-like proteins have thus existed for at least a half billion years, and must predate the evolutionary invention of bone and cartilage. Mutations in a Drosophila homolog of a BMP gene disrupt early dorsal/ventral patterning of the embryo and are lethal. These findings, together with data showing that mammalian BMPs are expressed in many different tissues during mouse development, suggest that the BMPs may play diverse roles in higher animals as well. Until recently, no mutations have been available to test the function of BMPs in vertebrates. However, this laboratory has recently shown that a BMP gene called Bmp-5 is defective in mice carrying mutations at the short ear locus. Complete loss of the gene is compatible with full viability and fertility of mice, but is associated with a specific syndrome of skeletal abnormalities including reduction of the external ear, loss of one pair of ribs, alterations in the size and shape of many bones, defects in repair of bone fractures, and a number of soft tissue abnormalities. This important mouse mutation provides the first genetic model for defining the roles of BMPs in the development of higher organisms. The proposed studies will determine how the expression pattern of Bmp-5 is related to the phenotypes seen in mutant mice, which domains of BMP molecules are most important for normal function, and what roles BMPs play outside the skeleton. Cis-acting sequences will be defined that control when and where the Bmp-5 osteoinductive signal is expressed during normal development. Finally, short ear mice will be used to test a new genetic approach for correcting skeletal defects using cloned BMP genes.