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About 30% of medulloblastomas (MBs), a tumor of the cerebellum, arise from cerebellar granule cell precursors (GCPs) undergoing transformation following activation of the Sonic hedgehog (Shh) pathway. To study this process, we generated a new MB model by crossing  Patched1  heterozygous ( Ptch1  +/− ) mice, which develop spontaneous Shh-type MBs, with mice lacking B-cell translocation gene 1 ( Btg1 ), a regulator of cerebellar development. In MBs developing in  Ptch1  +/−  mice, deletion of  Btg1  does not alter tumor and lesion frequencies, nor affect the proliferation of neoplastic precursor cells. However, in both tumors and lesions arising in  Ptch1  +/−  mice, ablation of  Btg1  increases by about 25% the apoptotic neoplastic precursor cells, as judged by positivity to activated caspase-3. Moreover, although  Btg1  ablation in early postnatal GCPs, developing in the external granule cell layer, leads to a significant increase of proliferation, and decrease of differentiation, relative to wild-type, no synergy occurs with the  Ptch1  +/−  mutation. However,  Btg1  deletion greatly increases apoptosis in postnatal GCPs, with strong synergy between  Btg1 -null and  Ptch1  +/−  mutations. That pronounced increase of apoptosis observed in  Ptch1  +/−  /Btg1  knockout young or neoplastic GCPs may be responsible for the lack of effect of  Btg1  ablation on tumorigenesis. This increased apoptosis may be a consequence of increased expression of protein arginine methyltransferase 1 (Prmt1) protein that we observe in  Btg1  knockout/ Ptch1  +/−  MBs. In fact, apoptotic genes, such as  BAD , are targets of Prmt1. Moreover, in  Btg1 -null MBs, we observed a two-fold increase of cells positive to CD15, which labels tumor stem cells, raising the possibility of activation of quiescent tumor cells, known for their role in long-term resistance to treatment and relapses. Thus,  Btg1  appears to play a role in cerebellar tumorigenesis by regulating the balance between apoptosis and proliferation during MB development, also influencing the number of tumor stem cells.

Deletion of Btg1 Induces Prmt1-Dependent Apoptosis and Increased Stemness in Shh-Type Medulloblastoma Cells Without Affecting Tumor Frequency