Generation of neuronal diversity from common progenitors via Notch signaling in the cerebellum

The bewildering diversity of brain neurons arises from relatively few pluripotent progenitors through poorly understood mechanisms. The cerebellum is an attractive model to investigate mechanisms of neuronal diversification because the different subtypes of excitatory and inhibitory neurons are well described. The cerebellum is a hub for control of motor function and contributes to a number of higher brain functions such as reward-related cognitive processes. Deficits in cerebellar development lead to severe neurological disorders such as cerebellar ataxias and medulloblastomas, a heterogeneous and severe groups of childhood brain tumors, thus underlying the importance of understanding the cellular and molecular control of cerebellar development. In contrast to text book models, we report that excitatory and inhibitory cerebellar neurons derive from the same pluripotent embryonic cerebellar stem cells (eCSC). We find that the excitatory versus inhibitory fate decision of a progenitor is regulated by Notch signaling, whereby the cell with lower Notch activity adopts the excitatory fate, while the cell with higher Notch activity adopts the inhibitory fate. Thus, Notch-mediated binary cell fate choice is a conserved strategy for generating neuronal diversity from common progenitors that is deployed at different developmental time points in a context specific manner.