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The Moonwalker (Mwk) mouse is a model of dominantly inherited cerebellar ataxia. The ataxic phenotype is caused by a gain-of-function mutation in the gene encoding the cation-permeable transient receptor potential channel TRPC3. Mwk mice display early-onset motor coordination defects and a loss of balance. TRPC3 is highly expressed in cerebellar Purkinje cells and type II unipolar brush cells that both degenerate in the adult Mwk mouse. In addition, Purkinje cells harboring the Mwk mutation do not develop normally and show reduced dendritic arborization and synaptogenesis. The Mwk mutation affects TRPC3 channel gating and results in altered excitability of Purkinje cells. Downstream effects include altered calcium homeostasis and changes in lipid metabolism. An increasing number of human spinocerebellar ataxias are associated with impairments of mGluR1-TRPC3 signaling, making the Mwk mouse a relevant disease model.

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AIMS Medulloblastoma (MB) comprises four main groups (SHH, WNT, group 3 and group 4), with distinct molecular, clinical and demographic features. These differences suggest opportunities for tailored and improved treatment. Despite its promise, translation into targeted therapy has been slow, limited by the lack of laboratory models that recapitulate patient tumours. Sporadic and inherited forms of SHH-MB are frequently due to mutations in the tumour suppressor gene PTCH1. Here, we aim to exploit human induced pluripotent stem cells (hiPSC) and CRISPR/Cas9 gene editing, to target PTCH1 in a clinically relevant context, thereby establishing an innovative model of MB. METHOD CRISPR/Cas9 mutation of PTCH1 in hiPSCs was followed by their differentiation into cerebellar organoids. Mutant organoids were studied for early consequences on cerebellar development and tumorigenesis. RESULTS PTCH1-mutation resulted in enhanced SHH-pathway activity in cerebellar organoids. Homozygous PTCH1-mutation prevented the formation of cerebellar progenitor cells, closely mimicking the effects of high SHH- signalling on neuronal progenitors in early embryonal development. Heterozygous PTCH1-mutant hiPSCs could be differentiated into cerebellar organoids, displayed increased growth rate and expressed oncogenes specific to SHH-MB, resembling preneoplasia and MB stem cells. CONCLUSION These results show that cerebellar organoids are a promising new model to study early oncogenic events in MB. Our model presents opportunities for the discovery of new targets which could benefit patients with a genetic predisposition to MB in particular. Refined knowledge of early drivers will be invaluable to guide drug selection and improve prospects for clinical translation.