Elucidation of the Underlying Causes of Tourette’s Syndrome Through Genetic Analysis of Forebrain Development

Grant Type
Basic
Grant Year
2000-2001
Institution Location
CA
Institution Organization Name
University of California
Investigators Name
Dye, Catherine, PhD

A major issue that remains enigmatic in the field of Gilles de la Tourette Syndrome (GTS) research concerns the underlying pathological defect. Although the etiology has been linked to dysfunction of the basal ganglia, currently no single developmental defect has been described that causes the disorder. To answer these questions, we must understand what makes the different groups of neurons unique. Not only in terms of how they function during communication in the adult, but also how they develop, and what factors promote their survival. Such an understanding can be achieved through characterization of the processes and mechanisms at work during CNS development and differentiation in a model system such as the mouse. The information obtained through such an analysis might then allow identification of cell-specific factors and signaling pathways to guide us in the design of treatment and intervention strategies. Previous studies of the Dlx (Distal-less like homeobox) genes, (which encode homeodomain-containing transcription factors) have demonstrated that several family members are key regulators of forebrain development. Two family members, Dlx 5 and 6, are expressed within the brain in regions that have shown to be affected in patients with GTS, such as the basal ganglia. By making distinct genetic changes in the Dlx genes of the mouse, I will disrupt the development and function of basal ganglia neurons. These mutant mice might display novel cognitive, behavioral or motor defects similar to those seen in patients with GTS. If successful, this might provide an avenue for development of pharmacological or even gene transfer-based treatment strategies for TS. As our body of knowledge about GTS expands, the mice will also serve as a useful reagent to other researchers interested in studying aspects of basal ganglia physiology relevant to this disorder. The long-term goals of my studies are to characterize how neuronal populations are born, what the molecular and functional differences are among individual types of neurons, and what developmental processes generate this diversity. In so doing, I hope to contribute to a framework of information that will allow us to characterize the nature of dysfunction in GTS. Catherine A. Dye, Ph.D. University of California, San Francisco, CA Award $25,000 * After this project was approved for TSA funding, Dr. Dye received notice of an NIH grant award in support of this work. TSA then provided her with partial, bridge funding until the initiation of her NIH funding. Tourette Association of America Inc. – Research Grant Award 2000-2001