Asymmetric centrosome inheritance maintains neural progenitors in the neocortex

Abstract

Asymmetric divisions of radial glia progenitors produce self-renewing radial glia and differentiating cells simultaneously in the ventricular zone (VZ) of the developing neocortex. Whereas differentiating cells leave the VZ to constitute the future neocortex, renewing radial glia progenitors stay in the VZ for subsequent divisions. The differential behaviour of progenitors and their differentiating progeny is essential for neocortical development; however, the mechanisms that ensure these behavioural differences are unclear. Here we show that asymmetric centrosome inheritance regulates the differential behaviour of renewing progenitors and their differentiating progeny in the embryonic mouse neocortex. Centrosome duplication in dividing radial glia progenitors generates a pair of centrosomes with differently aged mother centrioles. During peak phases of neurogenesis, the centrosome retaining the old mother centriole stays in the VZ and is preferentially inherited by radial glia progenitors, whereas the centrosome containing the new mother centriole mostly leaves the VZ and is largely associated with differentiating cells. Removal of ninein, a mature centriole-specific protein, disrupts the asymmetric segregation and inheritance of the centrosome and causes premature depletion of progenitors from the VZ. These results indicate that preferential inheritance of the centrosome with the mature older mother centriole is required for maintaining radial glia progenitors in the developing mammalian neocortex.

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Figure 1: Centriole and centrosome asymmetry in the developing neocortex.
Figure 2: Asymmetric segregation of centrosomes with differently aged mother centrioles.
Figure 3: Distinct behaviour of centrosomes with differently aged mother centrioles.
Figure 4: Asymmetric inheritance of centrosomes with differently aged mother centrioles.
Figure 5: Preferential inheritance of the centrosome with the mature mother centriole maintains radial glia progenitors.

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Acknowledgements

We thank A. Hall, A. L. Joyner, K. V. Anderson, J. Kaltschmidt, B. M. Tsou, Y. Chin and L. A. McDowell for comments on the manuscript; members of the Shi laboratory for discussions; A. K. Hadjantonakis for human centrin 1 cDNA; M. Bornens for EGFP–Nin (mouse) and Nin truncation mutant plasmids; Y.-R. Hong for EGFP–Nin (human) plasmid; A. Miyawaki for pCS2+–Kaede plasmid; and H. Zhong, K. Svoboda and R. Tsien for DsRedexpress and mPlum cDNA constructs. We thank C. T. Anderson and T. Stearns for sharing unpublished data. This work is supported by grants from March of Dimes Birth Defects Foundation, Whitehall Foundation, Dana Foundation, Autism Speaks Foundation, Klingenstein Foundation, NARSAD (to S.-H.S.) and NIH (to S.-H.S. and R.B.V.).

Author Contributions X.W. and S.-H.S. conceived the project. X.W. performed most of the experiments. J.-W.T., W.-N.L. and R.B.V. contributed to the time-lapse imaging experiment and J.H.I. contributed to the characterization of Kaede–CETN1 co-localization and in utero photoconversion procedure. X.W. and S.-H.S. analysed data, interpreted results and wrote the manuscript. All authors edited the manuscript.

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This file contains Supplementary Figures 1-16 with Legends and a Legend for Supplementary Video 1. (PDF 24650 kb)

Supplementary Video 1

This movie shows the distinct behaviour of centrosomes with differently aged mother centrioles in the developing neocortex (see file s1 for full Legend). (AVI 2479 kb)

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Wang, X., Tsai, J., Imai, J. et al. Asymmetric centrosome inheritance maintains neural progenitors in the neocortex. Nature 461, 947–955 (2009). https://doi.org/10.1038/nature08435

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