Abstract
We examined the role of the multi-pathway regulator GSK-3 in medulloblastoma pathogenesis in light of prior studies showing that GSK-3 restricts the proliferation of cerebral neural progenitors, preventing overgrowth. Importantly, 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 Gsk-3a -/-:Gsk-3β f/f mice with the Math1-cre transgenic line. We found that Gsk-3 deletion markedly reduced proliferation in the cerebellum, in striking contrast to the hyperproliferation induced by GSK-3 deletion in cortical progenitors. Transcription analysis by microarray revealed that hypoplasia was preceded by a strong activation of WNT signaling and up-regulation of CDKN1A (p21). Deleting Gsk-3 in medulloblastoma-prone SmoM2 mice also induced CDKN1A and markedly reduced tumor growth. These data show that GSK-3 is required for SHH-driven proliferation in both normal cerebellar progenitors and in SHH-driven medulloblastomas, where it functions to suppress WNT-mediated induction of CDKN1A. Based on our findings, we will test in our ongoing work whether GSK-3 inhibition, like Gsk-3 deletion, can block medulloblastoma growth, and produce a clinically significant anti-tumor effect.