Fig. 6: Model for Shh and Otx2-mediated regulation of cerebellar GCP proliferation in the context of normal development and medulloblastoma formation.

a During normal development, both Shh and Otx2 stimulate GCP proliferation through parallel signalling pathways. Ablation of Otx2 in this context, by shutting down of one of these pro-proliferative pathways, significantly impairs GCP proliferation, and leads to posterior cerebellum atrophy. b In the context of SmoM2 constitutive activation, forced Shh stimulation results in GCP overproliferation and the formation of type 2 medulloblastomas. This occurs whether Otx2 is present or absent, indicating that overactivation of the Shh pathway is dominant on the Otx2 pathway and is sufficient to promote tumour initiation in this context. b’ As they age, tumour cells become less responsive to Shh pathway signalling and more dependent on Otx2 signalling to sustain proliferation. Ablation of Otx2 in this context impairs cell proliferation and causes tumour regression. c In other (Shh-independent) types of medulloblastoma originating from GCPs, where the Shh pathway is not overactivated, such as type 3 medulloblastoma, proliferation mainly relies on the Otx2 alternative pathway: overexpression of Otx2 is frequently selected to ensure sustained proliferation of tumour cells