Distinct Smoothened mutation causes severe cerebellar developmental defects and medulloblastoma in a novel transgenic mouse model.

Publication Type:

Journal Article


Molecular and cellular biology (2012)


August 2012, Clinical Research Division


Deregulated developmental processes in the cerebellum cause medulloblastoma, the most common pediatric brain malignancy. About 25-30% of cases are caused by mutations increasing the activity of the Sonic hedgehog (Shh) pathway, a critical mitogen in cerebellar development. The proto-oncogene Smoothened (Smo) is a key transducer of the Shh pathway. Activating mutations in Smo that lead to constitutive activity of the Shh pathway have been identified in human medulloblastoma. To understand the developmental and oncogenic effects of two closely positioned point mutations in Smo, we characterized the NeuroD2:SmoA2 mice and compared them to NeuroD2:SmoA1 mice. While both SmoA1 and SmoA2 transgenes cause medulloblastoma with similar frequency and timing, the SmoA2 mice have severe aberrations in cerebellar development, whereas, the SmoA1 mice are largely normal during development. Intriguingly, neurologic function as measured by specific tests is normal in the SmoA2 mice despite extensive cerebellar dysplasia. We demonstrate how two nearly contiguous point mutations in the same domain of the encoded Smo protein can produce striking phenotypic differences in cerebellar development and organization in mice.