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.
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|Yip, Yee Ping; Mehta, Nisha; Magdaleno, Susan et al. (2009) Ectopic expression of reelin alters migration of sympathetic preganglionic neurons in the spinal cord. J Comp Neurol 515:260-8|
|Yip, Yee Ping; Capriotti, Christine; Drill, Emily et al. (2007) Cdk5 selectively affects the migration of different populations of neurons in the developing spinal cord. J Comp Neurol 503:297-307|
|Yip, Yee Ping; Kronstadt-O'Brien, Priscilla; Capriotti, Christine et al. (2007) Migration of sympathetic preganglionic neurons in the spinal cord is regulated by Reelin-dependent Dab1 tyrosine phosphorylation and CrkL. J Comp Neurol 502:635-43|
|Yip, Yee Ping; Zhou, Guangdou; Capriotti, Christine et al. (2004) Location of preganglionic neurons is independent of birthdate but is correlated to reelin-producing cells in the spinal cord. J Comp Neurol 475:564-74|
|Yip, Yee Ping; Capriotti, Christine; Magdaleno, Susan et al. (2004) Components of the reelin signaling pathway are expressed in the spinal cord. J Comp Neurol 470:210-9|
|Yip, Y P; Rinaman, L; Capriotti, C et al. (2003) Ectopic sympathetic preganglionic neurons maintain proper connectivity in the reeler mutant mouse. Neuroscience 118:439-50|
|Yip, Yee Ping; Capriotti, Christine; Yip, Joseph W (2003) Migratory pathway of sympathetic preganglionic neurons in normal and reeler mutant mice. J Comp Neurol 460:94-105|