Mutations in the Sonic Hedgehog (SHH) signalling pathway, including the SHH receptor PTCH1, are associated with medulloblastomas that frequently arise in very young children and have a relatively poor prognosis. Mouse models of this disease subtype have indicated that these tumours arise from granule neuronal precursor cells (GNPCs) of the cerebellum. By contrast, mutations in the Wnt pathway that involve β-catenin (encoded by CTNNB1) are common in medulloblastomas that develop in older children and these tumours generally have a good prognosis. However, whether Wnt-medulloblastomas also arise from GNPCs is unclear. To address this, Gibson and colleagues used four online gene expression databases that contained genes characteristic of SHH- or Wnt-medulloblastomas to map where in the brain these genes are expressed. To do this they used Brain Explorer 2, which maps gene expression in the mouse brain in three dimensions. The signature genes of SHH-medulloblastomas mapped to precursors in the developing mouse cerebellum and signature genes of Wnt-medulloblastomas mapped to precursors situated in the dorsal brain stem. If, as these results suggest, Wnt- and SHH-medulloblastomas arise in different cell populations, then they should be found in different regions of the hindbrain at diagnosis. Indeed, six medulloblastomas of the Wnt subtype were found attached to the dorsal brainstem and filling the IV ventricle, whereas SHH-medulloblastomas were found in the cerebella hemispheres.
SHH-medulloblastoma and Wnt-medulloblastoma are distinct diseases that involve different cells of origin.
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