New neurons continue to be born in the adult mammalian brain subventricular zone (SVZ) of the lateral ventricles and the subgranular layer (SGL) of the hippocampal dentate gyrus. Neural stem cells, cells that self-renew and generate neurons and glia, have been isolated from the SVZ and SGL with growth factors in vitro. The presence of neurogenic stem cells in the adult brain and the potential to manipulate these cells offers unprecedented opportunities for the replacement of brain cells lost in injury or disease. Recent work has identified the SVZ stem cell as Type B cell. Type B cells have the structure of astrocytes and express glial fibrillary acidic protein (GFAP). To understand the molecular regulation of adult neurogenesis, it is necessary to catalog the cell types and cell-cell interactions in these germinal zones, and describe the gene expression of the specific cell types. We thus propose the following Specific Aims: (1) To identify the cell types and architecture of the developing SVZ. Preliminary data suggests that cells containing a single specialized cilium in the ventricle walls of the juvenile animal are equivalent to the Type B cell in the adult. We present experiments to test this hypothesis. (2) To purify different SVZ cell types and construct representative cDNA libraries for each cell type. The libraries will be used to generate probes for GeneChip arrays to profile the gene expression of the major cell types of the adult SVZ. This experiment will be performed in collaboration with Affymetrix. Gene profiling data will be made available to the scientific community via the Internet. This data will reveal the molecular regulatory signals present in the SVZ cells as well as provide markers differentiating Type B cells from other brain astrocytes. (3) To investigate the cell types and architecture of the hippocampal SGL. The SGL stem cell will be identified using techniques similar to those used to identify the SVZ stem cell. Preliminary results suggest that SGL stem cells have properties in common with SVZ Type B cells. The combined knowledge of stem cell biology in the two major germinal regions of the adult brain will advance the ability to utilize adult-derived neural stem cells for brain repair.
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