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Asymmetric centrosome inheritance maintains neural progenitors in the neocortex

Nature volume 461, pages 947–955 (2009)Cite this article

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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References

  1. Miyata, T., Kawaguchi, A., Okano, H. & Ogawa, M. Asymmetric inheritance of radial glial fibers by cortical neurons. Neuron 31, 727–741 (2001)

    Article  CAS  Google Scholar 

  2. Noctor, S. C., Flint, A. C., Weissman, T. A., Dammerman, R. S. & Kriegstein, A. R. Neurons derived from radial glial cells establish radial units in neocortex. Nature 409, 714–720 (2001)

    Article  ADS  CAS  Google Scholar 

  3. Malatesta, P., Hartfuss, E. & Gotz, M. Isolation of radial glial cells by fluorescent-activated cell sorting reveals a neuronal lineage. Development 127, 5253–5263 (2000)

    CAS  Google Scholar 

  4. Rakic, P. Elusive radial glial cells: historical and evolutionary perspective. Glia 43, 19–32 (2003)

    Article  Google Scholar 

  5. Miyata, T. et al. Asymmetric production of surface-dividing and non-surface-dividing cortical progenitor cells. Development 131, 3133–3145 (2004)

    Article  CAS  Google Scholar 

  6. Noctor, S. C., Martinez-Cerdeno, V., Ivic, L. & Kriegstein, A. R. Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nature Neurosci. 7, 136–144 (2004)

    Article  CAS  Google Scholar 

  7. Chenn, A. & McConnell, S. K. Cleavage orientation and the asymmetric inheritance of Notch1 immunoreactivity in mammalian neurogenesis. Cell 82, 631–641 (1995)

    Article  CAS  Google Scholar 

  8. Noctor, S. C., Martinez-Cerdeno, V. & Kriegstein, A. R. Distinct behaviors of neural stem and progenitor cells underlie cortical neurogenesis. J. Comp. Neurol. 508, 28–44 (2008)

    Article  Google Scholar 

  9. Bornens, M. Centrosome composition and microtubule anchoring mechanisms. Curr. Opin. Cell Biol. 14, 25–34 (2002)

    Article  CAS  Google Scholar 

  10. Doxsey, S., McCollum, D. & Theurkauf, W. Centrosomes in cellular regulation. Annu. Rev. Cell Dev. Biol. 21, 411–434 (2005)

    Article  CAS  Google Scholar 

  11. Xie, Z. et al. Cep120 and TACCs control interkinetic nuclear migration and the neural progenitor pool. Neuron 56, 79–93 (2007)

    Article  CAS  Google Scholar 

  12. Tsai, J. W., Bremner, K. H. & Vallee, R. B. Dual subcellular roles for LIS1 and dynein in radial neuronal migration in live brain tissue. Nature Neurosci. 10, 970–979 (2007)

    Article  CAS  Google Scholar 

  13. Solecki, D. J., Model, L., Gaetz, J., Kapoor, T. M. & Hatten, M. E. Par6α signaling controls glial-guided neuronal migration. Nature Neurosci. 7, 1195–1203 (2004)

    Article  CAS  Google Scholar 

  14. Meraldi, P. & Nigg, E. A. The centrosome cycle. FEBS Lett. 521, 9–13 (2002)

    Article  CAS  Google Scholar 

  15. Delattre, M. & Gonczy, P. The arithmetic of centrosome biogenesis. J. Cell Sci. 117, 1619–1630 (2004)

    Article  CAS  Google Scholar 

  16. Lange, B. M. & Gull, K. A molecular marker for centriole maturation in the mammalian cell cycle. J. Cell Biol. 130, 919–927 (1995)

    Article  CAS  Google Scholar 

  17. Nakagawa, Y., Yamane, Y., Okanoue, T., Tsukita, S. & Tsukita, S. Outer dense fiber 2 is a widespread centrosome scaffold component preferentially associated with mother centrioles: its identification from isolated centrosomes. Mol. Biol. Cell 12, 1687–1697 (2001)

    Article  CAS  Google Scholar 

  18. Bouckson-Castaing, V. et al. Molecular characterisation of ninein, a new coiled-coil protein of the centrosome. J. Cell Sci. 109, 179–190 (1996)

    CAS  PubMed  Google Scholar 

  19. Ou, Y. Y., Mack, G. J., Zhang, M. & Rattner, J. B. CEP110 and ninein are located in a specific domain of the centrosome associated with centrosome maturation. J. Cell Sci. 115, 1825–1835 (2002)

    CAS  PubMed  Google Scholar 

  20. Piel, M., Meyer, P., Khodjakov, A., Rieder, C. L. & Bornens, M. The respective contributions of the mother and daughter centrioles to centrosome activity and behavior in vertebrate cells. J. Cell Biol. 149, 317–330 (2000)

    Article  CAS  Google Scholar 

  21. Anderson, C. T. & Stearns, T. Centriole age underlies asynchronous primary cilium growth in mammalian cells. Curr. Biol 10.1016/j.cub.2009.07.034 (12 August 2009)

  22. Chretien, D., Buendia, B., Fuller, S. D. & Karsenti, E. Reconstruction of the centrosome cycle from cryoelectron micrographs. J. Struct. Biol. 120, 117–133 (1997)

    Article  CAS  Google Scholar 

  23. Vorobjev, I. A. & Chentsov Yu. S Centrioles in the cell cycle. I. Epithelial cells. J. Cell Biol. 93, 938–949 (1982)

    Article  CAS  Google Scholar 

  24. Tsou, M. F. & Stearns, T. Mechanism limiting centrosome duplication to once per cell cycle. Nature 442, 947–951 (2006)

    Article  ADS  CAS  Google Scholar 

  25. Cheng, J. et al. Centrosome misorientation reduces stem cell division during ageing. Nature 456, 599–604 (2008)

    Article  ADS  CAS  Google Scholar 

  26. Yamashita, Y. M., Mahowald, A. P., Perlin, J. R. & Fuller, M. T. Asymmetric inheritance of mother versus daughter centrosome in stem cell division. Science 315, 518–521 (2007)

    Article  ADS  CAS  Google Scholar 

  27. Rebollo, E. et al. Functionally unequal centrosomes drive spindle orientation in asymmetrically dividing Drosophila neural stem cells. Dev. Cell 12, 467–474 (2007)

    Article  CAS  Google Scholar 

  28. Rusan, N. M. & Peifer, M. A role for a novel centrosome cycle in asymmetric cell division. J. Cell Biol. 177, 13–20 (2007)

    Article  CAS  Google Scholar 

  29. Stevens, N. R., Raposo, A. A., Basto, R., St Johnston, D. & Raff, J. W. From stem cell to embryo without centrioles. Curr. Biol. 17, 1498–1503 (2007)

    Article  CAS  Google Scholar 

  30. Cabernard, C. & Doe, C. Q. Stem cell self-renewal: centrosomes on the move. Curr. Biol. 17, R465–R467 (2007)

    Article  CAS  Google Scholar 

  31. Spradling, A. C. & Zheng, Y. Developmental biology. The mother of all stem cells? Science 315, 469–470 (2007)

    Article  CAS  Google Scholar 

  32. Yamashita, Y. M. & Fuller, M. T. Asymmetric centrosome behavior and the mechanisms of stem cell division. J. Cell Biol. 180, 261–266 (2008)

    Article  CAS  Google Scholar 

  33. Gonzalez, C. Spindle orientation, asymmetric division and tumour suppression in Drosophila stem cells. Nature Rev. Genet. 8, 462–472 (2007)

    Article  CAS  Google Scholar 

  34. Cox, J., Jackson, A. P., Bond, J. & Woods, C. G. What primary microcephaly can tell us about brain growth. Trends Mol. Med. 12, 358–366 (2006)

    Article  CAS  Google Scholar 

  35. Higginbotham, H. R. & Gleeson, J. G. The centrosome in neuronal development. Trends Neurosci. 30, 276–283 (2007)

    Article  CAS  Google Scholar 

  36. Hinds, J. W. & Ruffett, T. L. Cell proliferation in the neural tube: an electron microscopic and golgi analysis in the mouse cerebral vesicle. Z. Zellforsch. Mikrosk. Anat. 115, 226–264 (1971)

    Article  CAS  Google Scholar 

  37. Chenn, A., Zhang, Y. A., Chang, B. T. & McConnell, S. K. Intrinsic polarity of mammalian neuroepithelial cells. Mol. Cell. Neurosci. 11, 183–193 (1998)

    Article  CAS  Google Scholar 

  38. Bornens, M. & Piel, M. Centrosome inheritance: birthright or the privilege of maturity? Curr. Biol. 12, R71–R73 (2002)

    Article  CAS  Google Scholar 

  39. Ando, R., Hama, H., Yamamoto-Hino, M., Mizuno, H. & Miyawaki, A. An optical marker based on the UV-induced green-to-red photoconversion of a fluorescent protein. Proc. Natl Acad. Sci. USA 99, 12651–12656 (2002)

    Article  ADS  CAS  Google Scholar 

  40. Salisbury, J. L., Suino, K. M., Busby, R. & Springett, M. Centrin-2 is required for centriole duplication in mammalian cells. Curr. Biol. 12, 1287–1292 (2002)

    Article  CAS  Google Scholar 

  41. Cai, L., Hayes, N. L. & Nowakowski, R. S. Local homogeneity of cell cycle length in developing mouse cortex. J. Neurosci. 17, 2079–2087 (1997)

    Article  CAS  Google Scholar 

  42. Mogensen, M. M., Malik, A., Piel, M., Bouckson-Castaing, V. & Bornens, M. Microtubule minus-end anchorage at centrosomal and non-centrosomal sites: the role of ninein. J. Cell Sci. 113, 3013–3023 (2000)

    CAS  PubMed  Google Scholar 

  43. Delgehyr, N., Sillibourne, J. & Bornens, M. Microtubule nucleation and anchoring at the centrosome are independent processes linked by ninein function. J. Cell Sci. 118, 1565–1575 (2005)

    Article  CAS  Google Scholar 

  44. Bond, J. et al. A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size. Nature Genet. 37, 353–355 (2005)

    Article  CAS  Google Scholar 

  45. Preble, A. M., Giddings, T. M. & Dutcher, S. K. Basal bodies and centrioles: their function and structure. Curr. Top. Dev. Biol. 49, 207–233 (2000)

    Article  CAS  Google Scholar 

  46. Lambert, J. D. & Nagy, L. M. Asymmetric inheritance of centrosomally localized mRNAs during embryonic cleavages. Nature 420, 682–686 (2002)

    Article  ADS  CAS  Google Scholar 

  47. Wigley, W. C. et al. Dynamic association of proteasomal machinery with the centrosome. J. Cell Biol. 145, 481–490 (1999)

    Article  CAS  Google Scholar 

  48. Fuentealba, L. C., Eivers, E., Geissert, D., Taelman, V. & De Robertis, E. M. Asymmetric mitosis: unequal segregation of proteins destined for degradation. Proc. Natl Acad. Sci. USA 105, 7732–7737 (2008)

    Article  ADS  CAS  Google Scholar 

  49. Tabata, H. & Nakajima, K. Efficient in utero gene transfer system to the developing mouse brain using electroporation: visualization of neuronal migration in the developing cortex. Neuroscience 103, 865–872 (2001)

    Article  CAS  Google Scholar 

  50. Bultje, R. S. et al. Mammalian Par3 regulates progenitor cell asymmetric division via notch signaling in the developing neocortex. Neuron 63, 189–202 (2009)

    Article  CAS  Google Scholar 

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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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  1. Correspondence and requests for materials should be addressed to S.-H.S. (shis@mskcc.org).

Authors and Affiliations

  1. Developmental Biology Program, Memorial Sloan Kettering Cancer Centre, 1275 York Avenue, New York, New York 10065, USA ,

    Xiaoqun Wang, Janice H. Imai & Song-Hai Shi

  2. Departments of Pathology and Cell Biology, Columbia University, 630 W. 168th Street, New York, New York 10032, USA,

    Jin-Wu Tsai, Wei-Nan Lian & Richard B. Vallee

  3. BCMB Allied Program, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA ,

    Janice H. Imai & Song-Hai Shi

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Supplementary information

Supplementary Information

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, JW., 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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