Genetic and Molecular Determinants of Striatal Neurogenesis

Grant Type
Grant Year
Institution Location
Institution Organization Name
University of California
Investigators Name
Yun, Kyuson, PhD

Tourette Syndrome (TS) is a neuropsychiatric disorder characterized by chronic motor and vocal tics that begin in childhood. Family studies suggest that TS is inherited as a single autosomal dominant gene with variable penetrance. The discordance for symptom severity between identical twins has suggested that prenatal influences and other genetic interactions might modify the clinical expression of this disorder. Therefore, understanding the genetic and molecular regulation of early brain development is essential to understanding and identifying the genetic components that are either directly responsible for, or contribute to, the symptoms of TS. The goal of this project is to understand the regulatory events that control proper development of basal ganglia, a part of the brain which is implicated in the pathogenesis of TS. During the first year of TSA funding, I have identified and characterized a pathway, (well known in other systems to be important in making cell fate decisions [the Notch pathway]), that controls neurogenesis in the basal ganglia. It appears that the Notch pathway is mis-regulated in the Dlx1/2 mutant mice, which have a severe differentiation defect in the basal ganglia. We are in the process of summarizing these observations for a publication. Currently, we are focusing on genetic interactions between Dlx genes and Gsh genes which are also important for proper development of the basal ganglia. We believe that down-regulation of the Gsh genes by the Dlx genes is essential for differentiation of late-born neurons of the basal ganglia. It is possible that down-regulation of Gsh genes is closely linked to down-regulation of the Notch pathway (both require normal Dlx1/2 function). By studying mice that harbor mutations in the Dlx and Gsh genes, and by crossing these animals to create compound mutants, we are testing our working model of the genetic interactions that regulate striatal neurogenesis. It is our hope that understanding the genetic circuitry of basal ganglia development will lead to identification of gene(s) that are important in the understanding and treatment of TS. Kyuson Yun, Ph.D. University of California, San Francisco, CA Award $25,000(second year) Tourette Association of America Inc. – Research Grant Award 1999-2000