Activated Notch2 signaling inhibits differentiation of cerebellar granule neuron precursors by maintaining proliferation

In the developing cerebellar cortex, granule neuron precursors (GNPs) proli ferate and commence differentiation in a superficial zone, the external gra nule layer (EGL). The molecular basis of the transition from proliferating precursors to immature differentiating neurons remains unknown. Notch signa ling is an evolutionarily conserved pathway regulating the differentiation of precursor cells of many lineages. Notch2 is specifically expressed in pr oliferating GNPs in the EGL. Treatment of GNPs with soluble Notch ligand Ja gged1, or overexpression of activated Notch2 or its downstream target HES1, maintains precursor proliferation. The addition of GNP mitogens Jagged1 or Sonic Hedgehog (Shh) upregulates the expression of HES1, suggesting a role for HES1 in maintaining precursor proliferation.