Genetic Analysis of Bone Morphogenic Proteins

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DESCRIPTION (provided by applicant): Bone morphogenetic proteins (BMPs) are key signalling molecules that control many different steps in development. A large number of studies suggest that BMPs are the endogenous signals used by vertebrates to induce formation of cartilage and bone during embryonic development, and to stimulate repair of bone fractures in adults. More recent studies suggest that some BMP family members also play an important role in joint formation, and that BMP signalling may be required to maintain articular cartilage after birth. The remarkable ability of these proteins to induce the formation of new skeletal tissues when implanted at ectopic sites raises the possibility that they may form the basis of important new clinical treatments for fracture repair, spinal fusion, increased bone strength, and maintenance of articular cartilage. Despite the importance of BMPs in skeletal biology, very little is known about the molecular mechanisms that control where and when they are normally expressed. Increased understanding of this area may suggest new ways of manipulating BMP expression at particular sites and stages of development, or to inhibit BMP expression in diseases of ectopic bone formation. We are carrying out a detailed genetic, genomic, and functional study of the regulatory sequences that control expression of 3 different BMP genes during normal development. These studies have already shown that the regulatory sequences that control BMP expression are distributed over enormous distances around the coding sequences. The overall patterns of BMP expression are built up from a number of modular elements, each responsible for controlling expression in a small anatomical subset of the overall skeleton. We will use a combination of comparative sequencing, clone scanning, and functional tests in transgenic mice to identify minimal control elements responsible for BMP expression in the key proliferative layer that surrounds growing skeletal elements, and in interzones that mark the sites of joint formation. Transcription factors that act through these elements will be identified by a combination of expression screening and biochemical interaction with wild-type and mutant control elements. The isolated control elements will also be used to test the functional role of BMP signalling in controlling the size, shape, and curvature of ribs. Finally, joint specific control elements will be used to develop a general system for studying the role of other genes in joints.