| Humans diagnosed with glioblastoma, the highest grade and most malignant tumor of the astrocytic origin, have a poor prognosis of only six months to one year to live. Histological parameters are often used to uncover the cell(s) of origin and aid in the prognosis of patients. Specifically, nestin, an intermediate filament used as a marker for neuroprogenitor cells, is correlated with a high degree of cellular proliferation in these CNS tumors.; Transgenic mouse models have become a common in vivo experimental tool utilized to uncover and delineate genetic pathways and recapitulate human disease states. With the use of conditional transgenes, we can manipulate the spatial and temporal constraints under the direction of cell specific promoters. In order to engineer a mouse model of glioblastoma, an elegant strategy of cell cycle disruption in neuroprogenitor cells was initiated. Genetic mutations in the retinoblastoma family (pRbf) pathway are found in the majority of human gliomas (Schmidt E. E., et al., 1994) (Ueki K., et al. 1996). Therefore, the retinoblastoma family of cell cycle control proteins (pRb, p107 and p130) was inactivated by cell specific expression of the SV40 T-ag domain (T121) (Chen et al. 1992). It was concluded that pRbf inactivation under the nestin promoter is insufficient to induce tumorigenesis in this mouse model. Instead, an interesting developmental phenotype resulted that lead us to further investigate the role of pRbf in the developing CNS. Based on these data we suggest that the targeted cell population is the radial glial cell that guides cell migration and contributes to both the astrocytic and neuronal cell pool. Both the cortical and cerebellar tissues of the developing mouse were dramatically affected in this model. These studies have confirmed the importance of pRb in development while experimentally limiting redundancy of the pRb family members. This has become an interesting model, which contributes to both the developmental neuroscience and cancer research communities. |
