Many classical skeletal traits are known from previous phenotypic studies in mice. We have used chromosome walking and positional cloning techniques to identify the molecular basis of several classical mouse mutations that alter the size, shape, and number of specific bones and joints. Isolation of the short ear and brachypodism genes provided the first genetic evidence that bone morphogenetic proteins (BMPs) play an essential role in formation of both bone and joints, as well as in the repair of bone fractures in adult animals.

     BMPs have the remarkable ability to stimulate the entire process of cartilage and bone formation when expressed at new sites in mammals. Since BMPs are the key signals used by vertebrates to initiate skeletal formation in vivo, much of the pattern of the skeleton may be encoded by the regulatory sequences that lay out the expression of BMPs in specific patterns during embryonic development. We have used genetics, genomics, and comparative sequencing to identify a remarkable array of long distance, modular regulatory elements surrounding the Bmp5, Gdf5, and Gdf6 genes. These sequences correspond to individual "anatomy" elements that help control the size, shape, and number of individual bones and joints. Further study of these anatomy regulatory elements should provide a much more detailed picture of the molecular mechanisms that control the formation and patterning of the vertebrate skeleton. The control sequences are also providing important new tools for manipulating the expression of other genes in developing skeletal structures. For example, regulatory elements from the Gdf5 gene can be used to inactivate other genes specifically in joints, making it possible to identify genes and signals required for maintenance or repair of articular cartilage.

Projects:

1) Genes Controlling Formation of Bones and Joints in Mice

2) Skeletal Disease

3) Genetic Control of Vertebrate Evolution