DETERMINANTS OF PROGENITOR CELL FATE IN THE CNS

Previous studies on the rodent forebrain have defined a single precursor cell whose progeny can differentiate into two glial classes previously thought to arise from separate progenitors. Preliminary studies suggest that this precursor also has the potential to produce neurons as well as both glial lineages. The goal of this grant will be to determine the relative contributions of cell lineage and local environmental cues in shaping the fate of this cell's progeny. To establish the role of lineage in regulating fate, the following two hypotheses shall be tested: 1) that this precursor is genetically determined to divide asymmetrically to generate astroblasts and O-2A progenitors; and 2) that programmed cell death regulates the timing of postnatal gliogenesis by eliminating cells that develop inappropriately. To determine the role of cell-cell interactions in regulating cell fate, co-culture experiments will be performed with astrocytes, oligodendrocytes, neurons, and endothelial cells to test the hypothesis that contact with, or secreted growth factors from, these cells affect the differentiation of the multipotential precursor. To determine whether the same precursor that produces both classes of glia can also produce neurons, the multipotential glial precursor will be purified using immunoselection and grown in culture medium that fosters neuronal growth. A clonal analysis will establish whether this progenitor is pluripotent. Finally, the purified progenitor cell will be transplanted into fetal or juvenile hosts as another assay of its developmental potential. The outcome of these studies will profoundly influence current views on the development of the mammalian cerebral cortex. These studies will provide insights into the cellular origins of glial brain tumors and future characterizations of this precursor may provide insights that will assist the medical profession in treating individuals who suffer from neurological diseases and traumatic injuries to the nervous system.