A Distinct Smoothened Mutation Causes Severe Cerebellar Developmental Defects and Medulloblastoma in a Novel Transgenic Mouse Model

Deregulated developmental processes in the cerebellum cause medulloblastoma, the most common pediatric brain malignancy. About 25 to 30% of cases are caused by mutations increasing the activity of the Sonic hedgehog (Shh) pathway, a critical mitogen in cerebellar development. The proto-oncogeneSmoothened (Smo ) is a key transducer of the Shh pathway. Activating mutations inSmo 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 inSmo , we characterizedNeuroD2-SmoA2 mice and compared them toNeuroD2-SmoA1 mice. While bothSmoA1 andSmoA2 transgenes cause medulloblastoma with similar frequencies and timing,SmoA2 mice have severe aberrations in cerebellar development, whereasSmoA1 mice are largely normal during development. Intriguingly, neurologic function, as measured by specific tests, is normal in theSmoA2 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.