Generation of excitatory and inhibitory neurons from common progenitors via Notch signaling in the cerebellum

Brain neurons arise from relatively few progenitors generating an enormous diversity of neuronal types. Nonetheless, a cardinal feature of mammalian brain neurogenesis is thought to be that excitatory and inhibitory neurons derive from separate, spatially segregated progenitors. Whether bi-potential progenitors with an intrinsic capacity to generate both lineages exist and how such a fate decision may be regulated are unknown. Using cerebellar development as a model, we discover that individual progenitors can give rise to both inhibitory and excitatory lineages. Gradations of Notch activity determine the fates of the progenitors and their daughters. Daughters with the highest levels of Notch activity retain the progenitor fate, while intermediate levels of Notch activity generate inhibitory neurons, and daughters with very low levels of Notch signaling adopt the excitatory fate. Therefore, Notch-mediated binary cell fate choice is a mechanism for regulating the ratio of excitatory to inhibitory neurons from common progenitors. [Display omitted] •GABAergic and glutamatergic cerebellar neurons are generated from Sox2+ progenitors•Single Sox2+ ECPs can give rise to both excitatory and inhibitory cerebellar neurons•Notch activity mediates GABAergic versus glutamatergic cell fates in Sox2+ ECPs Zhang et al. report that excitatory and inhibitory neurons of the cerebellum can arise from individual embryonic cerebellar progenitors (ECPs). Notch activity controls the fate of bi-potential ECP daughters whereby cells with higher Notch activity adopt an inhibitory cell fate, whereas cells with lower Notch activity adopt an excitatory fate.