Medulloblastoma Arises from the Persistence of a Rare and Transient Sox2⁺ Granule Neuron Precursor

Medulloblastoma (MB) is a neoplasm linked to dysregulated cerebellar development. Previously, we demonstrated that the Sonic Hedgehog (SHH) subgroup grows hierarchically, with Sox2⁺ cells at the apex of tumor progression and relapse. To test whether this mechanism is rooted in a normal developmental process, we studied the role of Sox2 in cerebellar development. We find that the external germinal layer (EGL) is derived from embryonic Sox2⁺ precursors and that the EGL maintains a rare fraction of Sox2⁺ cells during the first postnatal week. Through lineage tracing and single-cell analysis, we demonstrate that these Sox2⁺ cells are within the Atoh1⁺ lineage, contribute extensively to adult granule neurons, and resemble Sox2⁺ tumor cells. Critically, constitutive activation of the SHH pathway leads to their aberrant persistence in the EGL and rapid tumor onset. We propose that failure to eliminate this rare but potent developmental population is the tumor initiation mechanism in SHH-subgroup MB.