Alongside the constitutive activation of Sonic hedgehog (SHH) pathway, SHH-subgroup medulloblastoma (MBSHH) is characterized by additional mutations, including those in chromatin modifier genes, highlighting the significance of additional hits in its progression. To comprehensively assess the oncogenic potential of these mutations, a flexible and versatile animal model is essential. Here, we utilize CRISPR-mediated gene editing via electroporation-based gene transfer to knockout the genes in cerebellar granule neuron progenitors of neonatal mice. By knocking out the Ptch1 gene at the neonatal stage, aberrant SHH activation is successfully induced, resulting in the formation of preneoplastic lesions and tumors. Of note, a simultaneous knockout of Ptch1 and additional genes of interest can be achieved by incorporating multiple single-guide RNA cassettes into one single expression vector, enabling evaluation of the role of genetic mutations in the MBSHH-prone context.