A critical question common to developmental neurobiology and molecular oncology is how progenitor cells integrate multiple extrinsic and intrinsic signals to decide whether to continue to proliferate or to exit the cell cycle and differentiate. During development of the nervous system, multipotent neural stem cells proliferate, give rise to a variety of lineage restricted precursor cells that then exit the cell cycle, mature and differentiate along specific cell lineages. Several molecules essential for guiding normal embryonic development continue to play a role in the mature nervous system and have recently been found to support the maintenance of stem cells. One such morphogen, Sonic hedgehog (Shh), which guides early formation of the somites and neural tube, has been found recently to promote proliferation of neural stem cells and is known to contribute to tumorigenesis in the gastrointestinal, skin and nervous systems. Aberrant regulation of Shh pathway components contributes to malignant transformation and are associated with almost half of all human malignancies. Data from our laboratory and others have demonstrated that activation of this pathway results in an expansion of the neural stem cell niche (Galvin et al. 2007) and also promotes spontaneous tumor development in the cerebellum (medulloblastoma)(Wetmore et al. 2000 and 2001). A major question that remains to be solved is how neural stem cells (NSCs) restrain their proliferation in an environment of chronic expression of the ligand, Shh. We have discovered that NSCs maintain a very narrow range of tolerated pathway activation and that enforced expression of the Gli1 transcription factor induces cell cycle arrest and apoptosis (Galvin et al. 2008) rather than proliferation. We are also interested in how neural stem and progenitor cells recognize and repair DNA damage and, thereby, avoid malignant transformation.

View a video: Cynthia Wetmore, M.D., Ph.D. discusses pediatric brain tumor research