Associate Professor, Faculty of Science, Department of Biological Sciences
University of Calgary
507 Campus Drive NW
Calgary, AB T2N 1N4
Different transcription factors are necessary for the development of specific segments of the limbs, and birth defects can result when the function of a transcription factor is missing. For example, we have found that the mouse gene Shox2 is necessary to form the proximal segment of the limbs (the humerus in the arms and the femur in the legs). Shox2 is closely related to a human gene called SHOX whose disruption causes the malformed limbs in people with Turner, Léri-Weill and Langer syndromes, which together affect approximately 1 in 1,000 people. Patients with these syndromes all have a characteristic shortening in the middle portion of the limbs, the radius/ulna of the arms and the tibia/fibula of the legs. Therefore, both human SHOX patients and Shox2-mutant mice develop with shortened limbs, although the phenotypes are restricted to different segments of the limbs. We hypothesize that mouse Shox2 and human SHOX have similar cellular functions that are exerted in different parts of the embryo according to where the genes are expressed. Therefore, we are studying how Shox2 controls limb development as a model for human SHOX function. We also study how these genes are regulated since SHOX-deficient phenotypes can be caused by deletions that leave the coding sequence of the SHOX gene intact. These deletions most likely remove regulatory elements called enhancers-DNA sequences that control the expression of genes in specific tissues during development. However, since these effects occur in humans, direct demonstration of this function is difficult. We have produced transgenic mice that directly test whether specific sequences near Shox genes (human SHOX and mouse Shox2) mediate enhancer activity. Most notably, we have used our transgenic mouse assay to demonstrate the limb-specific activity of a human enhancer from a region frequently deleted in SHOX patients. We are expanding on this finding with the goal of gaining a comprehensive understanding of how expression of the SHOX gene is regulated.