The long term goal of this study is to understand how mammalian CNS neurons and glia are generated. The murine cerebral cortex contains a large number of restricted neuronal progenitor cells at very early stages of embryogenesis. The remaining cells are multi-potent stem cells that are capable of generating both neurons and glia. An small number at early stages are restricted glial progenitors. Despite their relative rarity, cortical stem cells appear to be a major source of neurons and the major source of glia at early times. This proposal aims to examine how cortical stem cells are regulated so that they generate appropriate neuronal and glial progeny through development. The approach that has been developed in the applicant's lab has been to use clonal cultures in which the fates of individual cells are followed in detail with the use of time lapse video analysis. Thus, the entire lineage tress of cells in culture for extended periods of times can be followed and manipulated under the controlled conditions of the in vitro environment. The action of selected environmental factors (such as BMP and various trophic factors) on neuron or glial production will be examined. Diverse types of neurons and glia arise over time in these cultures and these will be followed step-by-step (with an emphasis on glial lineages) as differentiated cells are generated from the cloned progenitor cells. Also candidate genes that may play a pivotal role in neuron or glial generation in the developing cerebral cortex will be investigated. In particular, the expression of the vertebrate homologue Drosophila neural lineages, will be assessed in cortical neuroblast lineages using antibodies. An interesting gene known as glial cells missing will be examined as the lineages switch dramatically and spontaneously from making neurons to making largely glial.
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