Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Neurogenic radial glia in the outer subventricular zone of human neocortex

Nature volume 464, pages 554–561 (2010)Cite this article

Subjects

This article has been updated

Abstract

Neurons in the developing rodent cortex are generated from radial glial cells that function as neural stem cells. These epithelial cells line the cerebral ventricles and generate intermediate progenitor cells that migrate into the subventricular zone (SVZ) and proliferate to increase neuronal number. The developing human SVZ has a massively expanded outer region (OSVZ) thought to contribute to cortical size and complexity. However, OSVZ progenitor cell types and their contribution to neurogenesis are not well understood. Here we show that large numbers of radial glia-like cells and intermediate progenitor cells populate the human OSVZ. We find that OSVZ radial glia-like cells have a long basal process but, surprisingly, are non-epithelial as they lack contact with the ventricular surface. Using real-time imaging and clonal analysis, we demonstrate that these cells can undergo proliferative divisions and self-renewing asymmetric divisions to generate neuronal progenitor cells that can proliferate further. We also show that inhibition of Notch signalling in OSVZ progenitor cells induces their neuronal differentiation. The establishment of non-ventricular radial glia-like cells may have been a critical evolutionary advance underlying increased cortical size and complexity in the human brain.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The human OSVZ is populated with non-epithelial radial glia-like cells.
Figure 2: oRG cells self-renew and produce intermediate progenitor daughter cells.
Figure 3: Daughters of oRG cells are neuronal progenitors.
Figure 4: The human OSVZ is the predominant neurogenic zone during mid-gestational cortical development.
Figure 5: OSVZ progenitors require Notch signalling to remain undifferentiated.

Change history

  • 25 March 2010

    Fig. 4 was changed to double column on 25 March 2010.

References

  1. Smart, I. H. Proliferative characteristics of the ependymal layer during the early development of the mouse neocortex: a pilot study based on recording the number, location and plane of cleavage of mitotic figures. J. Anat. 116, 67–91 (1973)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  2. 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  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. 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  PubMed  Google Scholar 

  5. Haubensak, W., Attardo, A., Denk, W. & Huttner, W. B. Neurons arise in the basal neuroepithelium of the early mammalian telencephalon: a major site of neurogenesis. Proc. Natl Acad. Sci. USA 101, 3196–3201 (2004)

    Article  ADS  CAS  PubMed  PubMed Central  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  PubMed  Google Scholar 

  7. Smart, I. H., Dehay, C., Giroud, P., Berland, M. & Kennedy, H. Unique morphological features of the proliferative zones and postmitotic compartments of the neural epithelium giving rise to striate and extrastriate cortex in the monkey. Cereb. Cortex 12, 37–53 (2002)

    Article  PubMed  Google Scholar 

  8. Zecevic, N., Chen, Y. & Filipovic, R. Contributions of cortical subventricular zone to the development of the human cerebral cortex. J. Comp. Neurol. 491, 109–122 (2005)

    Article  PubMed  PubMed Central  Google Scholar 

  9. Fish, J. L., Dehay, C., Kennedy, H. & Huttner, W. B. Making bigger brains-the evolution of neural-progenitor-cell division. J. Cell Sci. 121, 2783–2793 (2008)

    Article  CAS  PubMed  Google Scholar 

  10. Rakic, P. Neurons in rhesus monkey visual cortex: systematic relation between time of origin and eventual disposition. Science 183, 425–427 (1974)

    Article  ADS  CAS  PubMed  Google Scholar 

  11. Lukaszewicz, A. et al. G1 phase regulation, area-specific cell cycle control, and cytoarchitectonics in the primate cortex. Neuron 47, 353–364 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bayatti, N. et al. A molecular neuroanatomical study of the developing human neocortex from 8 to 17 postconceptional weeks revealing the early differentiation of the subplate and subventricular zone. Cereb. Cortex 18, 1536–1548 (2008)

    Article  PubMed  Google Scholar 

  13. Mo, Z. & Zecevic, N. Is Pax6 critical for neurogenesis in the human fetal brain? Cereb. Cortex 18, 1455–1465 (2008)

    Article  PubMed  Google Scholar 

  14. Götz, M., Stoykova, A. & Gruss, P. Pax6 controls radial glia differentiation in the cerebral cortex. Neuron 21, 1031–1044 (1998)

    Article  PubMed  Google Scholar 

  15. Haas, K., Sin, W. C., Javaherian, A., Li, Z. & Cline, H. T. Single-cell electroporation for gene transfer in vivo . Neuron 29, 583–591 (2001)

    Article  CAS  PubMed  Google Scholar 

  16. Weissman, T., Noctor, S. C., Clinton, B. K., Honig, L. S. & Kriegstein, A. R. Neurogenic radial glial cells in reptile, rodent and human: from mitosis to migration. Cereb. Cortex 13, 550–559 (2003)

    Article  PubMed  Google Scholar 

  17. Rakic, P. Developmental and evolutionary adaptations of cortical radial glia. Cereb. Cortex 13, 541–549 (2003)

    Article  PubMed  Google Scholar 

  18. Rakic, P. Specification of cerebral cortical areas. Science 241, 170–176 (1988)

    Article  ADS  CAS  PubMed  Google Scholar 

  19. Gan, W. B., Grutzendler, J., Wong, W. T., Wong, R. O. & Lichtman, J. W. Multicolor “DiOlistic” labeling of the nervous system using lipophilic dye combinations. Neuron 27, 219–225 (2000)

    Article  CAS  PubMed  Google Scholar 

  20. 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  PubMed  Google Scholar 

  21. Letinic, K., Zoncu, R. & Rakic, P. Origin of GABAergic neurons in the human neocortex. Nature 417, 645–649 (2002)

    Article  ADS  CAS  PubMed  Google Scholar 

  22. Englund, C. et al. Pax6, Tbr2, and Tbr1 are expressed sequentially by radial glia, intermediate progenitor cells, and postmitotic neurons in developing neocortex. J. Neurosci. 25, 247–251 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kowalczyk, T. et al. Intermediate neuronal progenitors (basal progenitors) produce pyramidal-projection neurons for all layers of cerebral cortex. Cereb. Cortex 19, 2439–2450 (2009)

    Article  PubMed  PubMed Central  Google Scholar 

  24. Sessa, A., Mao, C. A., Hadjantonakis, A. K., Klein, W. H. & Broccoli, V. TBR2 directs conversion of radial glia into basal precursors and guides neuronal amplification by indirect neurogenesis in the developing neocortex. Neuron 60, 56–69 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Petanjek, Z., Berger, B. & Esclapez, M. Origins of cortical GABAergic neurons in the cynomolgus monkey. Cereb. Cortex 19, 249–262 (2009)

    Article  PubMed  Google Scholar 

  26. Götz, M. & Huttner, W. B. The cell biology of neurogenesis. Nature Rev. Mol. Cell Biol. 6, 777–788 (2005)

    Article  Google Scholar 

  27. Gaiano, N., Nye, J. S. & Fishell, G. Radial glial identity is promoted by Notch1 signaling in the murine forebrain. Neuron 26, 395–404 (2000)

    Article  CAS  PubMed  Google Scholar 

  28. Shimojo, H., Ohtsuka, T. & Kageyama, R. Oscillations in Notch signaling regulate maintenance of neural progenitors. Neuron 58, 52–64 (2008)

    Article  CAS  PubMed  Google Scholar 

  29. Abdel-Mannan, O., Cheung, A. F. & Molnar, Z. Evolution of cortical neurogenesis. Brain Res. Bull. 75, 398–404 (2008)

    Article  CAS  PubMed  Google Scholar 

  30. Rakic, P. & Sidman, R. L. Supravital DNA synthesis in the developing human and mouse brain. J. Neuropathol. Exp. Neurol. 27, 240–276 (1968)

    Article  Google Scholar 

  31. Choi, B. H. Glial fibrillary acidic protein in radial glia of early human fetal cerebrum: a light and electron microscopic immunoperoxidase study. J. Neuropathol. Exp. Neurol. 45, 408–418 (1986)

    Article  CAS  PubMed  Google Scholar 

  32. Schmechel, D. E. & Rakic, P. Arrested proliferation of radial glial cells during midgestation in rhesus monkey. Nature 277, 303–305 (1979)

    Article  ADS  CAS  PubMed  Google Scholar 

  33. Schmechel, D. E. & Rakic, P. A Golgi study of radial glial cells in developing monkey telencephalon: morphogenesis and transformation into astrocytes. Anat. Embryol. (Berl.) 156, 115–152 (1979)

    Article  CAS  Google Scholar 

  34. Kriegstein, A., Noctor, S. & Martinez-Cerdeno, V. Patterns of neural stem and progenitor cell division may underlie evolutionary cortical expansion. Nature Rev. Neurosci. 7, 883–890 (2006)

    Article  CAS  Google Scholar 

  35. Baek, J. H., Hatakeyama, J., Sakamoto, S., Ohtsuka, T. & Kageyama, R. Persistent and high levels of Hes1 expression regulate boundary formation in the developing central nervous system. Development 133, 2467–2476 (2006)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank A. Alvarez-Buylla, D. Rowitch and Kriegstein laboratory members for ideas arising from discussions and for critical reading of the manuscript. We thank A. Javaherian for help setting up the conditions for dye electroporation, T. Weissman for advice on ‘DiOlistics’, Z. Mirzadeh for expertise with whole-mount staining, C. Harwell for retroviral production, and W. Walantus, J. Agudelo, L. Fuentealba, O. Genbacev, M. Donne and S. Kaing for other technical support. We thank R. Kageyama for his gift of the HES1 antibody35, and F. Gage for GFP-retrovirus reagents. We thank the staff at San Francisco General Hospital for providing access to donated fetal tissue. Artwork in Fig. 5e is by K. X. Probst (Xavier Studio). This work was supported by grants from the California Institute for Regenerative Medicine and the Bernard Osher Foundation. J.H.L. is funded by a CIRM Predoctoral Fellowship.

Author Contributions D.V.H. and J.H.L. (listed alphabetically) carried out all the experiments except for the electrophysiology, analysed the data, and wrote the manuscript. P.R.L.P. performed the electrophysiology and analysed data. A.R.K., as the principal investigator, provided conceptual and technical guidance for all aspects of the project. All authors discussed the results/experiments and revised/edited the manuscript.

Author information

Author notes

  1. David V. Hansen and Jan H. Lui: These authors contributed equally to this work.

Authors and Affiliations

  1. Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research,,

    David V. Hansen, Jan H. Lui, Philip R. L. Parker & Arnold R. Kriegstein

  2. Department of Neurology,,

    David V. Hansen, Jan H. Lui, Philip R. L. Parker & Arnold R. Kriegstein

  3. Biomedical Sciences Graduate Program,,

    Jan H. Lui

  4. Neuroscience Graduate Program, University of California San Francisco, 513 Parnassus Avenue, San Francisco, California 94143, USA ,

    Philip R. L. Parker

Authors
  1. David V. Hansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jan H. Lui
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Philip R. L. Parker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Arnold R. Kriegstein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Arnold R. Kriegstein.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-14 with Legends and Legends for Supplementary Movies 1-4. (PDF 28812 kb)

Supplementary Movie 1

This movie shows multiple examples of mitotic somal translocation and oRG (OSVZ radial glia-like) cell division. Imaging for ~20 h at 20-min intervals - see Supplementary Information file for full legend. (MOV 5651 kb)

Supplementary Movie 2

This movie shows an oRG cell division highlighting mitotic somal translocation, followed by division of intermediate progenitor daughter. Imaging for ~46 h at 22-min intervals. Cell divisions are at t=12:18 and t=45:46 - see Supplementary Information file for full legend. (MOV 4955 kb)

Supplementary Movie 3

This movie shows an oRG cell that divides and self-renews twice. Imaging for ~56 h at 22-min intervals. Cell divisions are at t=0:44 and t=44:38 - see Supplementary Information file for full legend. (MOV 7008 kb)

Supplementary Movie 4

This movie shows an oRG cell undergo two self-renewing divisions followed by an intermediate progenitor daughter cell division. Imaging for ~57 h at 22-min intervals. Cell divisions are at t=5:30, t=43:32, and t=46:50 - see Supplementary Information file for full legend. (MOV 6139 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hansen, D., Lui, J., Parker, P. et al. Neurogenic radial glia in the outer subventricular zone of human neocortex. Nature 464, 554–561 (2010). https://doi.org/10.1038/nature08845

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature08845

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing