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The timing of cortical neurogenesis is encoded within lineages of individual progenitor cells

Nature Neuroscience volume 9, pages 743–751 (2006)Cite this article

Abstract

In the developing cerebral cortex, neurons are born on a predictable schedule. Here we show in mice that the essential timing mechanism is programmed within individual progenitor cells, and its expression depends solely on cell-intrinsic and environmental factors generated within the clonal lineage. Multipotent progenitor cells undergo repeated asymmetric divisions, sequentially generating neurons in their normal in vivo order: first preplate cells, including Cajal-Retzius neurons, then deep and finally superficial cortical plate neurons. As each cortical layer arises, stem cells and neuroblasts become restricted from generating earlier-born neuron types. Growth as neurospheres or in co-culture with younger cells did not restore their plasticity. Using short-hairpin RNA (shRNA) to reduce Foxg1 expression reset the timing of mid- but not late-gestation progenitors, allowing them to remake preplate neurons and then cortical-plate neurons. Our data demonstrate that neural stem cells change neuropotency during development and have a window of plasticity when restrictions can be reversed.

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Figure 1: Timing of appearance of diverse cortical neurons.
Figure 2: Time-lapse lineage analysis of embryonic mouse cortical progenitor cells.
Figure 3: Cortical neuroblasts and stem cells from different embryonic stages show progressive restriction in neuropotency.
Figure 4: shRNAFoxg1 treatment of E12 cortical cells enhances neurogenesis but impairs gliogenesis.
Figure 5: E12 cortical cells divide asymmetrically and generate Reelin+ neurons after shRNAFoxg1 treatment.

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Acknowledgements

We thank L. Jin, S.K. Goderie, N. Lowry, B. Lewis, B. Roysam, P. Lederman and C. Butler for technical assistance and T. Miyata, H. Tang, J. Cunningham, C. Walsh, S. Morton, S. Arber and T. Jessell for their generous donation of antibodies. This work was supported by grant number R37NS033529 from the National Institute of Neurological Disorders and Stroke.

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Authors and Affiliations

  1. Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, 12208, New York, USA

    Qin Shen, Yue Wang, Christopher A Fasano, Timothy N Phoenix & Sally Temple

  2. Department of Molecular Biology, Princeton University, Princeton, 08544, New Jersey, USA

    John T Dimos, Ihor R Lemischka & Natalia B Ivanova

  3. Center for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, H3A 2B4, Quebec, Canada

    Stefano Stifani

  4. Department of Medicine and Molecular Cardiology Research Center, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Edward E Morrisey

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Supplementary information

Supplementary Fig. 1

Cortical stem cells grown as neurospheres show restriction in neuropotency. (PDF 1309 kb)

Supplementary Fig. 2

Reelin+ neuron production after lentiviral transduction. (PDF 66 kb)

Supplementary Fig. 3

Reduction of Olig2 expression after shRNAFoxg1 treatment. (PDF 76 kb)

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Shen, Q., Wang, Y., Dimos, J. et al. The timing of cortical neurogenesis is encoded within lineages of individual progenitor cells. Nat Neurosci 9, 743–751 (2006). https://doi.org/10.1038/nn1694

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