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 described1,2. The cerebellum is a hub for control of motor function and contributes to a number of higher brain functions such as reward-related cognitive processes3. Deficits in cerebellar development lead to severe neurological disorders such as cerebellar ataxias4 and medulloblastomas5, 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.
This work was supported by the program “Investissements d’avenir” ANR-10-IAIHU-06, ICM, (to B.A.H.), Armenise-Harvard Foundation, AIRC and CARITRO (to L.T.) and the European Research Council (to S.H.) Work in the Hippenmeyer laboratory was also supported by the under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 725780 LinPro) to S.H. T.T.Z., T.Y.L. were supported by doctoral fellowships form the China Scholarship Council and A.H.H. by a doctoral fellowship of the Austrian Academy of Sciences. Light microscopy work was carried out at ICM’s imaging core facility, ICM.Quant, and analysis of scRNAseq data was carried out at ICM’s bioinofmrtaics core facility, iCONICS. We thank Paulina Ejsmont, Natalia Danda and Nathalie De Geest for technical support. We are grateful to Dr. Shahragim TAJBAKHSH for providing R26Rstop-NICD- nGFP transgenic mice, Dr. Bart De Strooper for Presenilin1 deficient mice. We also thanks to Dr. Mikio Hoshino for providing Atoh1 and Ptf1a antibodies. B.A.H. is an Allen Distinguished Investigator and an Einstein Visiting Fellow of the Berlin Institute of Health.
Zhang T, Liu T, Mora N, et al. Generation of neuronal diversity from common progenitors via Notch signaling in the cerebellum. bioRxiv. doi:10.1101/2020.03.18.997205
Zhang, T., Liu, T., Mora, N., Guegan, J., Bertrand, M., Contreras, X., … Hassan, B. A. (n.d.). Generation of neuronal diversity from common progenitors via Notch signaling in the cerebellum. bioRxiv. Cold Spring Harbor Laboratory. https://doi.org/10.1101/2020.03.18.997205
Zhang, Tingting, Tengyuan Liu, Natalia Mora, Justine Guegan, Mathilde Bertrand, Ximena Contreras, Andi H Hansen, et al. “Generation of Neuronal Diversity from Common Progenitors via Notch Signaling in the Cerebellum.” BioRxiv. Cold Spring Harbor Laboratory, n.d. https://doi.org/10.1101/2020.03.18.997205.
T. Zhang et al., “Generation of neuronal diversity from common progenitors via Notch signaling in the cerebellum,” bioRxiv. Cold Spring Harbor Laboratory.
Zhang T, Liu T, Mora N, Guegan J, Bertrand M, Contreras X, Hansen AH, Streicher C, Anderle M, Tiberi L, Hippenmeyer S, Hassan BA. Generation of neuronal diversity from common progenitors via Notch signaling in the cerebellum. bioRxiv, 10.1101/2020.03.18.997205.
Zhang, Tingting, et al. “Generation of Neuronal Diversity from Common Progenitors via Notch Signaling in the Cerebellum.” BioRxiv, Cold Spring Harbor Laboratory, doi:10.1101/2020.03.18.997205.