Journal
DEVELOPMENT
Volume 131, Issue 1, Pages 217-228Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.00891
Keywords
cerebellum; Sonic hedgehog; proliferation; GSK3; medulloblastoma; Myc; neural precursor; mouse; Nmyc1 (N-myc)
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Funding
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R21NS041764] Funding Source: NIH RePORTER
- NINDS NIH HHS [R01 NS4051, R21 NS41764-01] Funding Source: Medline
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Neuronal precursor cells in the developing cerebellum require activity of the sonic hedgehog (Shh) and phosphoinositide-3-kinase (PI3K) pathways for growth and survival. Synergy between the Shh and PI3K signaling pathways are implicated in the cerebellar tumor medulloblastoma. Here, we describe a mechanism through which these disparate signaling pathways cooperate to promote proliferation of cerebellar granule neuron precursors. Shh signaling drives expression of mRNA encoding the Nmyc1 oncoprotein (previously N-myc), which is essential for expansion of cerebellar granule neuron precursors. The PI3K pathway stabilizes Nmyc1 protein via inhibition of GSK3-dependent Nmyc1 phosphorylation and degradation. The effects of PI3K activity on Nmyc1 stabilization are mimicked by insulin-like growth factor, a PI3K agonist with roles in central nervous system precursor growth and tumorigenesis. These findings indicate that Shh and PI3K signaling pathways converge on N-Myc to regulate neuronal precursor cell cycle progression. Furthermore, they provide a rationale for therapeutic targeting of PI3K signaling in medulloblastoma.
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