Tumorigenesis and embryogenesis share many molecular players and pathways, including the sonic hedgehog (Shh) signalling pathway. In a new study, Kenney et al. have identified a downstream target of Shh that is involved in both neurogenesis and tumorigenesis in the cerebellum.
Nmyc is a proto-oncogene that is amplified in certain brain tumours, including the cerebellar tumour medulloblastoma. Circumstantial evidence has indicated that Shh and Nmyc might be functionally linked — for example, Knoepfler et al. recently showed that Nmyc is required for normal neurogenesis in the cerebellum, a process that also depends on Shh. Also, blocking Hedgehog signalling has been shown to inhibit medulloblastoma growth. Now, Kenney et al. have discovered the nature of this functional relationship.
The authors found that Shh upregulates Nmyc expression in cerebellar granule neuron precursors (CGNPs) in vitro. Using transgenic embryos, they showed that Nmyc is upregulated ectopically in the dorsal spinal cord when Shh expression is driven by a Wnt1 regulatory element. Two further observations indicated that Nmyc acts downstream of Shh. Overexpression of Nmyc activated G1 cyclins in CGNPs and stimulated ongoing proliferation, independent of Shh activity. Shh also promoted CGNP proliferation, but its potency was reduced by the addition of a Myc antagonist.
These findings indicate that Nmyc is a direct downstream target of Shh that mediates its effects on cell proliferation during cerebellar development and in medulloblastomas. The upregulation of Nmyc by Shh seems to be context-dependent, as Nmyc is expressed in the cerebellar granule cell precursor layer, but not in the floorplate, which is another key site of Shh expression. This finding represents a significant step in piecing together a signalling pathway that is important to both neuroscientists and cancer biologists.
References
ORIGINAL RESEARCH PAPERS
Kenney, A. M. et al. Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors. Development 130, 15–28 (2002)
FURTHER READING
Knoepfler, P. S. et al. N-myc is essential during neurogenesis for the rapid expansion of progenitor cell populations and the inhibition of neuronal differentation. Genes Dev. 16, 2699–2712 (2002)
Berman, D. M. et al. Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 297, 1559–1561 (2002)
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Wood, H. A new target for Hedgehog. Nat Rev Neurosci 4, 8 (2003). https://doi.org/10.1038/nrn1017
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DOI: https://doi.org/10.1038/nrn1017