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First published online 3 December 2003
doi: 10.1242/dev.00891

Development 131, 217-228 (2004)
Published by The Company of Biologists 2004
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Hedgehog and PI-3 kinase signaling converge on Nmyc1 to promote cell cycle progression in cerebellar neuronal precursors

Anna Marie Kenney1, Hans R. Widlund1 and David H. Rowitch1,2,*

1 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA
2 Divison of Newborn Medicine, Children's Hospital, Boston, MA 02115, USA

* Author for correspondence (e-mail: david_rowitch{at}dfci.harvard.edu)

Accepted 30 September 2003

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.

Key words: Cerebellum, Sonic hedgehog, Proliferation, GSK3, Medulloblastoma, Myc, Neural precursor, Mouse, Nmyc1 (N-myc)


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