We now know that neural stem cells persist in restricted regions of the adult human brain. The subventricular zone (SVZ) is the largest such region, yet in humans its function remains unknown. In contrast to every other studied vertebrate, including primates, the human SVZ does not appear to generate neurons for the olfactory bulb, but contains a robust ribbon of multipotent, self-renewing astrocytic neural stem cells that lines the lateral ventricles. Unfortunately, nearly every study of the human SVZ is based upon adult tissue. The proposed work will characterize the cellular composition and transcriptional expression patterns of fetal and pediatric human germinal zones. Using a combination of tissue histology, electron microscopy, and cell culture techniques, we will define the cytoarchitecture of these regions and identify their progenitor populations. Concurrently, through a functional genomics approach, we will determine the spatial and stage-specific expression of essential transcription factors selected through DNA microarray analysis. Our hypothesis is that progenitor cells of the developing human SVZ can be identified by combinatorial expression of transcription factors. A corollary of this hypothesis is that such transcription factors may also regulate the fate and potential of such cells in vivo. This combined phenotypic and genotypic study of fetal and pediatric human germinal zones will not only identify novel human neural stem cell populations and migratory streams, but will also highlight the molecular pathways conserved across human neural stem development and pediatric brain tumor formation. The emerging connection between developmental neurobiology and neuro-oncology suggests that pediatric human brain tumors such as brainstem gliomas may be driven by underlying progenitor cell populations. Pediatric brainstem gliomas represent 10-25% of all pediatric intracranial tumors and typically carry a very poor prognosis. Defining the structure and function of developing human germinal regions may clarify the role neural stem cells play in pediatric tumorigenesis. ? ?
| Sanai, Nader; Nguyen, Thuhien; Ihrie, Rebecca A et al. (2011) Corridors of migrating neurons in the human brain and their decline during infancy. Nature 478:382-6 |
