Divergent functions for eIF4E and S6 kinase by sonic hedgehog mitogenic signaling in the developing cerebellum

Cerebellar development entails rapid peri-natal proliferation of cerebellar granule neuron precursors (CGNPs), proposed cells-of-origin for certain medulloblastomas. CGNPs require insulin-like growth factor (IGF) for survival and sonic hedgehog (Shh)-implicated in medulloblastoma-for proliferation. The IGF-responsive kinase mammalian target of rapamycin (mTOR) drives proliferation-associated protein synthesis. We asked whether Shh signaling regulates mTOR targets to promote CGNP proliferation despite constitutive IGF signaling under proliferative and differentiation-promoting conditions. Surprisingly, Shh promoted eukaryotic initiation factor 4E (eIF4E) expression, but inhibited S6 kinase (S6K). In vivo, S6K activity specifically marked the CGNP population transitioning from proliferation-competent to post-mitotic. Indeed, eIF4E was required for CGNP proliferation, while S6K activation drove cell cycle exit. Protein phosphatase 2A (PP2A) inhibition rescued S6K activity. Moreover, Shh upregulated the PP2A B56γ subunit, which targets S6K for inactivation and was required for CGNP proliferation. These findings reveal unique developmental functions for eIF4E and S6 kinase wherein their activity is specifically uncoupled by mitogenic Shh signaling.