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doi: 10.1242/10.1242/dev.00182
1 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard
Medical School, Boston, MA 02115, USA
2 Department of Molecular Biology, Princeton University, Princeton, NJ 08544,
USA
3 Division of Newborn Medicine, Children's Hospital, Boston MA 02115, USA
* Author for correspondence (e-mail: david_rowitch{at}dfci.harvard.edu)
Accepted 2 October 2002
Hedgehog pathway activation is required for expansion of specific neuronal precursor populations during development and is etiologic in the human cerebellar tumor, medulloblastoma. We report that sonic hedgehog (Shh) signaling upregulates expression of the proto-oncogene Nmyc in cultured cerebellar granule neuron precursors (CGNPs) in the absence of new protein synthesis. The temporal-spatial expression pattern of Nmyc, but not other Myc family members, precisely coincides with regions of hedgehog proliferative activity in the developing cerebellum and is observed in medulloblastomas of Patched (Ptch) heterozygous mice. Overexpression of Nmyc promotes cell-autonomous G1 cyclin upregulation and CGNP proliferation independent of Shh signaling. Furthermore, Myc antagonism in vitro significantly decreases proliferative effects of Shh in cultured CGNPs. Together, these findings identify Nmyc as a direct target of the Shh pathway that functions to regulate cell cycle progression in cerebellar granule neuron precursors.
Key words: Cerebellum, Sonic hedgehog, Proliferation, Cyclopamine, Medulloblastoma, Nmyc, Neural precursor, TRRAP, Mouse
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