Mice are the preeminent model system for mammalian genetics, combining relatively short generation times, ready avaialability of many inbred and mutant lines, and sophisticated methods for making precise knockouts and gene substitutions. Mice are also often the best system available for asking detailed mechanistic questions in mammals, or testing the phenotypic effects of particular sequence changes seen in mice or other species. We have used classical genetics in mice to identify fundamental pathways that control the formation and patterning of cartilage, bone, and joints (Kingsley 1992, Storm 1994, Storm and Kingsley 1996, Ho et al. 2000). We also make extensive use of mice for identifying the regulatory mechanisms that lay out expression of key developmental control genes, with the ultimate aim of identifying how vertebrate morphology itself is encoded in the genome (DiLeone et al. 1998, 2000; Mortlock et al. 2003, Menke et al. 2008, Guenther et al. 2008).
Our positional cloning of the classic mouse 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 (Kingsley et al. 1992; Storm et al. 1994; 1996) . 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 (Kingsley 1994). 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. (DiLeone et al. 1998, 2000; Mortlock et al. 2003; Rountree et al. 2004; Guenther et al. 2008). 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 will provide a much more detailed picture of the molecular mechanisms that control the formation and patterning of the vertebrate skeleton (Guenther et al. 2008). 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 (Rountree et al. 2004; Gurley et al. 2006; Koyama et al. 2007, Kahn et al. 2009).
Many genes in vertebrates are controlled by the same kind of complex, long distance regulatory apparatus we have worked out in detail for BMP genes. We are currently using a set of methods worked out in our BMP studies (BAC scanning, comparative sequence analys, transgenic enhancer assays, and targeted modification of regulatory sequences ) to indentify the regulatory apparatus controlling expression of several other key developmental control genes. These studies are identifying how vertebrates control separate growth of forelimb and hindlimb structures (Menke et al. 2008, Chan et al. 2009), and how major changes in external appearance can arise through regulatory changes controlling stem cell factor signaling (Miller et al. 2007).
More information on research projects in sticklebacks and humans.