Many neurological disorders including schizophrenia and some forms of childhood epilepsy arise as a consequence of migratory defects during brain development. A gene that has been found to influence neuronal migration in the brain of the mouse is the reeler gene (reln). Although reln has now been cloned and the protein (Reelin) that it encodes has been identified, the mechanism by which Reelin affects neuronal migration is still unclear. The proposed studies will use sympathetic preganglionic neuronal migration as a model system to investigate the function of Reelin and the role of its signaling pathway in control of neuronal migration. The analysis of sympathetic preganglionic neuronal migration is appropriate for studies of Reelin function on neuronal positioning during development for a number of reasons: 1) Sympathetic preganglionic neurons form a discrete population that responds to Reelin. 2) The duration of preganglionic migration is short and the pathway can be well defined. 3) The migration of preganglionic neurons is amenable to quantitative analysis as proposed in the present research. 4) Migrating preganglionic neurons can be retrogradely labeled and identified in cell or explant cultures, making it possible to study the molecular mechanisms of Reelin signaling in vitro. 5) The mode of action of Reelin on preganglionic neuronal migration can be investigated in the slice culture through a variety of perturbation experiments that cannot be applied to brain development. Proposed studies will combine the expertise of 2 established investigators (Drs. T. Curran and J. Yip) to analyze the molecular and cellular basis of Reelin function.
Specific aims of the proposed research are to: 1) Analyze the migration of sympathetic preganglionic neurons as a model system for investigating Reelin function. 2) Use preganglionic neuronal migration as a model system to determine the role of Reelin in neuronal migration. 3) Investigate the role of the Reelin signaling pathway in control of preganglionic cell migration. Results will provide important insights on the molecular and cellular basis of Reelin function, and may reveal significant information about the mechanisms responsible for devastating diseases caused by abnormal migration.
