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Progenitor cell maintenance requires numb and numblike during mouse neurogenesis

Abstract

Neurons in most regions of the mammalian nervous system are generated over an extended period of time during development. Maintaining sufficient numbers of progenitors over the course of neurogenesis is essential to ensure that neural cells are produced in correct numbers and diverse types1,2,3. The underlying molecular mechanisms, like those governing stem-cell self-renewal in general, remain poorly understood. We report here that mouse numb and numblike (Nbl)4,5,6, two highly conserved homologues of Drosophila numb7,8, play redundant but critical roles in maintaining neural progenitor cells during embryogenesis, by allowing their progenies to choose progenitor over neuronal fates. In Nbl mutant embryos also conditionally mutant for mouse numb in the nervous system, early neurons emerge in the expected spatial and temporal pattern, but at the expense of progenitor cells, leading to a nearly complete depletion of dividing cells shortly after the onset of neurogenesis. Our findings show that a shared molecular mechanism, with mouse Numb and Nbl as key components, governs the self-renewal of all neural progenitor cells, regardless of their lineage or regional identities.

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Figure 1: Conditional double knockout of mouse numb and Nbl.
Figure 2: Effect of mouse numb and Nbl conditional double mutation on neurogenesis.
Figure 4: Motor neuron generation at the expense of progenitor cells.
Figure 3: Effect of mouse numb and Nbl conditional double mutation on neurogenesis before neural tube thinning.
Figure 5: Neuron overproduction and death in mouse numb and Nbl conditional double-mutant embryos.

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Acknowledgements

We thank members of the Zhong laboratory for discussions, C. Jacobs and H. Keshishian for comments, K. Jakobsdottir for support (P.H.P.), J. Zhang for technical assistance, Developmental Studies Hybridoma Bank, D. Anderson, R. Kageyama, U. Lendahl, M. Lewandoski, M. Nakafuku, H. Takebayashi and M. Wegner for reagents. K.Z. is supported by a Yale Anderson fellowship. Y.N.J. is a HHMI investigator. This work was supported by a Yale Hellman Family fellowship and grants from March of Dimes and NINDS to W.Z. and from NIMH to the Silvio Conte Center for Neuroscience Research at UCSF.

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Correspondence to Weimin Zhong.

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Petersen, P., Zou, K., Hwang, J. et al. Progenitor cell maintenance requires numb and numblike during mouse neurogenesis. Nature 419, 929–934 (2002). https://doi.org/10.1038/nature01124

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