Generation of Neuronal Diversity from Common Progenitors Via Notch Signaling in the Cerebellum

The diversity of brain neurons arises from relatively few pluripotent progenitors. In both the Drosophila and mammalian brains individual progenitors use temporal transitions mechanisms to generate different neuronal subtypes over time. In Drosophila further neuronal diversity is achieved by a binary cell fate choice mechanism mediated by the Notch signaling pathway. However, there is no evidence for Notch-based neuronal diversification in the mammalian brain. Using mouse and human cerebellar development as a model, we discover that individual embryonic cerebellar progenitors give rise to both inhibitory and excitatory lineages. We find that gradations of Notch activity levels determine the fates of the progenitors and their daughters. Daughters with the highest levels of Notch activity retain the progenitor fate. Daughters with intermediate levels of Notch activity become fate restricted to generate inhibitory neurons, while daughters with very low levels of Notch signaling adopt the excitatory fate. Therefore, Notch-mediated binary cell fate choice is a mechanism for generating neuronal diversity in the mammalian brain, and thus a widespread mechanism of neuronal diversification.