The goal of these studies is to further our understanding of the molecular signals that govern oligodendrocyte differentiation in the developing nervous system. The approach we will use focuses on the characterization of a novel neurological mutant, the weebler (wb), recently identified in our animal colony. Preliminary data indicate this is an autosomal recessive mutation, which primarily causes a loss of cerebellar Purkinje cells. Our findings indicate that this mutant has unique clinical and pathological features that have not been previously described in the literature, although it has many features comparable to other Purkinje cell degeneration mutants. In the wb mouse, the loss of Purkinje cells has a dramatic effect on oligodendrocyte differentiation in the cerebellum. We propose to investigate the mechanism by which the loss of these neurons affects oligodendrocytes. We will initially focus on investigating the mechanism by which oligodendrocyte differentiation is reduced and how oligodendrocyte gene expression changes with development in these animals. This will determine whether the mutation has a direct, deleterious effect on the oligodendrocyte, or whether the oligodendrocyte pathology results from a loss of target cells and abnormal development. In addition to our studies in vivo, we will investigate the interaction between oligodendrocytes and Purkinje cells in vitro. We will also study the effects of other Purkinje cell degeneration mutants, PCD and nervous, on oligodendrocyte differentiation. These mutants appear to induce Purkinje cell degeneration at different stages than the wb mutation, and we will assess similarities and differences in their effects on oligodendrocytes.
Our final aim will be to map the mutation, since identifying the gene that is mutated in the wb mouse is essential to understanding how the mutation generates developmentally altered Purkinje cells and changes in oligodendrocyte differentiation. These studies should significantly advance our understanding of the interaction of oligodendrocytes and neurons, and the neuronal signals that are needed to induce normal oligodendrocyte differentiation.
| Duchala, Cynthia S; Shick, H Elizabeth; Garcia, Jessica et al. (2004) The toppler mouse: a novel mutant exhibiting loss of Purkinje cells. J Comp Neurol 476:113-29 |
