David Kingsley, Ph.D.

Associate Professor of Developmental Biology,

Assistant Investigator of the Howard Hughes Medical Institute

My laboratory is using genetics and genomics to study the mechanisms that create and pattern skeletal tissues in higher animals. We have chosen the skeleton because it provides one of the most dramatic examples of spatial and morphological patterning in vertebrates, is extensively modified in different animals, and plays a key role in human health and disease. Many of our studies have begun with the laboratory mouse, where large collections of classical skeletal traits are known that disrupt the formation and repair of specific skeletal features. We have used modern positional cloning techniques to isolate the genes responsible for several of these traits, including genes that control the formation of somites during early development, the number of digits that form in the limb, the condensation of mesenchyme into outlines of future skeletal elements, the repair of skeletal structures after injury in adult animals, or the formation and maintenance of joints in different regions of the body. These studies have identified some of the key molecules used by embryos to induce formation of cartilage and bone, control segmentation, and to prevent arthritis in joints after birth. We are currently studying a human mutations in the same genes that underlie a variety of different skeletal diseases. We are also using transgenic mice to study the regulation of several of these genes, with a particular interest in understanding the regulatory pathways that make it possible to independently modifiy the size and shape of individual skeletal elements. Finally, we have recently launched a major effort to characterize the genetic mechanisms that are responsible for modification of skeletal structures during vertebrate evolution. Threespine sticklebacks are an extensively studied small teleost fish that have undergone a remarkable evolutionary radiation in postglacial lakes created only 10,000 years ago. Despite dramatic differences in behavior, body size, shape, color, skeletal patterns, and fin development; fish from different lakes can still be crossed to study the genetic basis of repeated morphological evolution. We have built a complete genome wide linkage map of this organism, and are currently using it to identify the number and location of genes that control the appearence of new traits during vertebrate evolution. Initial results suggest that some of the dramatic differences between recently evolved fish populations are due to a few major chromosome regions. It should be possible to use this system to determine the types of genes involved in evolutionary modification of form and behavior, whether the key changes occur in coding or regulatory regions, and whether evolution of similar traits occurs by the same or different mechanisms in independent lakes around the world.