Journal
DEVELOPMENT
Volume 130, Issue 1, Pages 15-28Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.00182
Keywords
cerebellum; sonic hedgehog; proliferation; cyclopamine; medulloblastoma; Nmyc; neural precursor; TRRAP; mouse
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Funding
- NINDS NIH HHS [R21 NS41764-01, R01 NS4051] Funding Source: Medline
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R21NS041764] Funding Source: NIH RePORTER
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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 protooncogene 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 G(1) 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.
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