Abnormal lamination of the cerebral cortex is presumed to result from an interference with neuronal migration during development. Despite recent gains in our understanding of normal development, analysis of the pathogenesis of migrational abnormalities has been limited by the inaccessibility of mammalian embryos and by our inability to directly visualize the abnormal migratory patterns. Recently, however, recombinant retroviruses have been developed that allow neural progenitors to be labeled at any stage of embryogenesis. The progeny of single infected cells can be visualized by histochemical staining and their routes of migration discerned from their arrangement as they leave their birthplace. Retroviral studies of normal migration within the chick optic tectum have allowed detection of even small numbers of atypically migrating cells. The tectum is a tissue that shares many structural, functional, and morphogenetic features with the mammalian cortex, yet is more accessible to injection of virus and to experimental manipulation during early development. It therefore has the potential to serve as an excellent model system in which to study the pathogenesis of migrational abnormalities. The immediate goals are to determine whether lamination and migration in the chick optic tectum are disrupted by hypoxia, radiation, infarction, toxins, and surgical manipulation, and to determine whether the migrational changes account for the induced pathology. Migratory pathways will be assessed with recombinant retroviruses, and routine histological stains, cell type-specific antibodies, electron microscopy and axonal tracing methods will be used to detect pathology. A combination of iodo- and bromodeoxyuridine labeling will be employed to determine the relationship between a cell's birthdate and position. A novel retroviral marker and Dil will be used to learn if malpositioned neurons have abnormal axonal projections. The major question to be answered is whether discrete types of migrational abnormalities cause specific classes of lamination defects. The long term goal is to establish a system not only in which to screen potential teratogens for their effects on the neuronal migration but also in which the mechanisms of action of these agents may be determined.
