David Kingsley

Research/Lab website:   http://kingsley.stanford.edu

The skeleton is one of the most highly patterned structures in higher organisms. Although built of only a few tissue types, these tissues are molded into beautiful shapes and sizes that illustrate many basic problems in development, morphogenesis, and vertebrate evolution. The skeleton is also critical to human health, with diseases like osteoarthritis and osteoporosis afflicting a large fraction of the human population. To better understand the genetic mechanisms that create, pattern, and repair skeletal tissues, we are using both forward and reverse genetic approaches to study interesting skeletal traits in humans, mice, and stickleback fish.

We have used a combination of high resolution linkage mapping and chromosome walking techniques to isolate several classical mouse skeletal mutations that disrupt skeletal patterning or joint formation. These studies have shown that secreted signalling molecules called bone morphogenetic proteins (BMPs) play a key role in controlling formation of both bones and joints during embryonic development. Each of these genes is expressed in strikingly specific patterns that prefigure the formation of particular bones and joints. We have used detailed transgenic and comparative genomic methods to identify the regulatory elements responsible for patterning the expression of these genes during vertebrate skeletal development. The long term goal of these studies is to determine how the body creates, shapes, and maintains particular bones and joints in order to generate a functional skeleton.

We have also used genetic methods to isolate a completely new gene controlling susceptibility to arthritis after birth. The normal product of this gene is a highly conserved multiple pass transmembrane protein found only in vertebrates. We have used a combination of cell culture and biochemical techniques to show that this molecule acts by stimulating transport of the same small molecule that is used in “tartar control” toothpaste to block unwanted mineral and calc deposits along the gum line. Mutations in the gene block elaboration of the mineralization inhibitor, leading to ectopic formation of crystals in the articular cartilage and synovial fluid, and development of arthritis. Similar ectopic mineral deposition is seen in a large fraction of the elderly human population, and may be an important risk factor for human arthritis.

Finally, we are using genetic crosses between recently evolved fish species to study the molecular basis of vertebrate evolution. For this work we have launched a major initiative to develop genetic and genomic resources for threespine sticklebacks, a small teleost fish that has undergone one of the most recent and dramatic evolutionary radiations on earth. Thousands of distinct types of sticklebacks have evolved in newly created streams and lakes at the end of the last Ice Age, with major changes in body size, skeletal armor, feeding apparatus, salt and temperature preference, color, and behavior. The reproductive barriers between fish can be overcome using in vitro ferilization, providing a unique opportunity to study the genetic basis of evolutionary change. To take advanatge of this system, we htave already built the first genome-wide genetic and physical maps of sticklebacks, mapped many different traits, identified some of the genes responsible for evolutionary change, and rescued traits using transgenic approaches. Based on this progress, and extensive previous studies of stickleback biology, NIH is planning to complete a stickleback genome sequence in 2005. We expect sticklebacks to become one of the major new model systems for studying the genetic basis of complex traits in natural populations, and one of the only vertebrates where it is possible to determine how many genes are required to evolve a new traits, what kinds of mutations occur in those genes, and whether nature uses similar mechanisms to evolve similar traits in independent locations.