MB-10: GSK-3 PROMOTES PROLIFERATION DURING POSTNATAL CEREBELLAR DEVELOPMENT AND MAY BE TARGETED IN MEDULLOBLASTOMA THERAPY

In light of prior studies showing that GSK-3 is required to prevent overgrowth of cerebral neural progenitors, we examined whether deletion of GSK-3 in the cerebellum would produce hyperplasia and support medulloblastoma tumorigenesis. GSK-3 regulates diverse intracellular processes, including signaling through Wnt and N-myc, which have both been implicated in tumorigenesis. We deleted both isoforms of GSK-3 conditionally in the cerebellum by crossing GSKα -/-:GSKβ f/f mice with the Math1-cre transgenic line. We found that GSK-3 deletion induced marked hypoproliferation in the cerebellum, contrary to the hyperproliferation seen when GSK in deleted in cortical progenitors. Transcription analysis by microarray revealed that hypoplasia was preceded by a strong activation of WNT signaling. Deleting GSK-3 in medulloblastoma-prone SmoM2 mice markedly reduced tumor growth. Ongoing studies will determine if WNT signaling is activated in GSK-deleted tumors and may mediate the reduced growth. Our data show that the predominant effect of GSK-3 during cerebellar development and medulloblastoma formation is to promote growth, and that disruption of GSK-3 function may exert a significant restriction on tumor growth.