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Neurogenic radial glia in the outer subventricular zone of human neocortex

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

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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.

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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.

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Change history

  • 25 March 2010

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

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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.

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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

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  1. David V. Hansen
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Corresponding author

Correspondence to Arnold R. Kriegstein.

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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)

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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

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