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Local generation of glia is a major astrocyte source in postnatal cortex

Nature volume 484, pages 376–380 (2012)Cite this article

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Abstract

Glial cells constitute nearly 50% of the cells in the human brain1. Astrocytes, which make up the largest glial population, are crucial to the regulation of synaptic connectivity during postnatal development2. Because defects in astrocyte generation are associated with severe neurological disorders such as brain tumours3, it is important to understand how astrocytes are produced. Astrocytes reportedly arise from two sources4,5,6: radial glia in the ventricular zone and progenitors in the subventricular zone, with the contribution from each region shifting with time. During the first three weeks of postnatal development, the glial cell population, which contains predominantly astrocytes, expands 6–8-fold in the rodent brain7. Little is known about the mechanisms underlying this expansion. Here we show that a major source of glia in the postnatal cortex in mice is the local proliferation of differentiated astrocytes. Unlike glial progenitors in the subventricular zone, differentiated astrocytes undergo symmetric division, and their progeny integrate functionally into the existing glial network as mature astrocytes that form endfeet with blood vessels, couple electrically to neighbouring astrocytes, and take up glutamate after neuronal activity.

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Figure 1: Locally generated glia as a major source of astrocytes.
Figure 2: Properties of dividing cells within the cortex.
Figure 3: Time-lapse imaging of local proliferation of astrocytes.
Figure 4: Symmetric division of proliferating astrocytes and the function of their progeny.

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Acknowledgements

We thank K. D. McCarthy and H. Zeng for providing us with the hGFAP-CreER and Ai14 transgenic mice, respectively; A. Sakaue-Sawano for the CAG-Fucci-Green transgenic mice; M. Stryker, Y. Xiang, X.-q. Wang, S. Barbel, J.-d. Chen, W. Zhou, F. Huang, and members of the Jan laboratory for discussion; G.-n. Li for help on electroporation; Y. Li for advice on retroviral experiments; and E. Unger, C Guo, H. Yang, Q. Deng, J. Berg and X-y. Li for reading the manuscript. W.-P.G. is a recipient of a Long-Term Fellowship of Human Frontier Science Program (HFSP) and National Institute of Neurological Disorders and Stroke (NINDS) Pathway to Independence Award. This work was supported by a NINDS K99/R00 award (1K99NS073735) to W.-P.G., a National Institute of Mental Health R37 grant (4R37MH065334) to L.Y.J, a National Institutes of Health (NIH) R01 grant (5R01MH084234) to Y.N.J., and grants from the NIH/National Institute on Aging P01 AG010435, MH090258, Jeffry M. and Barbara Picower Foundation (JBP) and McDonnell Foundation to F.H.G. L.Y.J. and Y.N.J. are Howard Hughes Medical Institute investigators.

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Authors and Affiliations

  1. Departments of Physiology, Howard Hughes Medical Institute, Biochemistry and Biophysics, University of California at San Francisco, 1550 4th Street, San Francisco, California 94158, USA,

    Woo-Ping Ge, Yuh Nung Jan & Lily Yeh Jan

  2. Life Function and Dynamics, Exploratory Research for Advanced Technology, Japan Science and Technology Agency, and Brain Science Institute, RIKEN, Wako-city, Saitama, 351-0198, Japan ,

    Atsushi Miyawaki

  3. Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, 92037, California, USA

    Fred H. Gage

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  1. Woo-Ping Ge
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  2. Atsushi Miyawaki
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Contributions

W.-P.G. conceived the project, designed and performed the experiments and analysed the data. L.Y.J. and Y.N.J. supervised the work and helped to design the experiments. W.-P.G. and L.Y.J. wrote the manuscript. F.H.G. and A.M. provided MLV retrovirus and CAG-Fucci-Green transgenic mice, respectively. All authors reviewed and edited the manuscript.

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Correspondence to Lily Yeh Jan.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-14 and Supplementary Table 1. (PDF 11538 kb)

Supplementary Movie 1

A movie showing local division of astrocytes in a cortical slice (cortical layers I-IV) from a P3 hGFAP-GFP tg mouse. Total time of the movie is 2 hr 46 min. (MOV 2430 kb)

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Ge, WP., Miyawaki, A., Gage, F. et al. Local generation of glia is a major astrocyte source in postnatal cortex. Nature 484, 376–380 (2012). https://doi.org/10.1038/nature10959

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