Letter | Published:

Radial glia require PDGFD–PDGFRβ signalling in human but not mouse neocortex

Nature volume 515, pages 264268 (13 November 2014) | Download Citation

Abstract

Evolutionary expansion of the human neocortex underlies many of our unique mental abilities. This expansion has been attributed to the increased proliferative potential1,2 of radial glia (RG; neural stem cells) and their subventricular dispersion from the periventricular niche3,4,5 during neocortical development. Such adaptations may have evolved through gene expression changes in RG. However, whether or how RG gene expression varies between humans and other species is unknown. Here we show that the transcriptional profiles of human and mouse neocortical RG are broadly conserved during neurogenesis, yet diverge for specific signalling pathways. By analysing differential gene co-expression relationships between the species, we demonstrate that the growth factor PDGFD is specifically expressed by RG in human, but not mouse, corticogenesis. We also show that the expression domain of PDGFRβ, the cognate receptor6,7 for PDGFD, is evolutionarily divergent, with high expression in the germinal region of dorsal human neocortex but not in the mouse. Pharmacological inhibition of PDGFD–PDGFRβ signalling in slice culture prevents normal cell cycle progression of neocortical RG in human, but not mouse. Conversely, injection of recombinant PDGFD or ectopic expression of constitutively active PDGFRβ in developing mouse neocortex increases the proportion of RG and their subventricular dispersion. These findings highlight the requirement of PDGFD–PDGFRβ signalling for human neocortical development and suggest that local production of growth factors by RG supports the expanded germinal region and progenitor heterogeneity of species with large brains.

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Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

Microarray data from the GCASS dataset have been deposited in Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under accession number GSE62064.

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Acknowledgements

We thank the staff at San Francisco General Hospital Women’s Options Center for their consideration in allowing access to donated human prenatal tissue. We thank J. DeYoung and the staff at the Southern California Genotyping Consortium at the University of California Los Angeles for microarray data generation. We are grateful to A. Holloway for her critical reading of the manuscript, and also thank W. Walantus, S. Wang, Y. Wang and other University of California San Francisco personnel for technical and administrative support. We thank C. Stiles and D. Rowitch for the TEL–PDGFRβ construct. This work was supported by grants from the NIH, NINDS (A.R.K.), the Bernard Osher Foundation, a California Institute for Regenerative Medicine Predoctoral Fellowship for J.H.L. (TG2-01153), a Damon Runyon Foundation Postdoctoral Fellowship for A.A.P. (DRG-2013), and the University of California San Francisco Program for Breakthrough Biomedical Research, which is funded in part by the Sandler Foundation (M.C.O.). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the California Institute for Regenerative Medicine or any other agency of the State of California.

Author information

Author notes

    • Jan H. Lui
    •  & Tomasz J. Nowakowski

    These authors contributed equally to this work.

    • Jan H. Lui
    •  & Ashkan Javaherian

    Present addresses: Department of Biology and Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA (J.H.L.); Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA (A.J.).

    • Arnold R. Kriegstein
    •  & Michael C. Oldham

    These authors jointly supervised this work.

Affiliations

  1. Department of Neurology and The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California 94143, USA

    • Jan H. Lui
    • , Tomasz J. Nowakowski
    • , Alex A. Pollen
    • , Ashkan Javaherian
    • , Arnold R. Kriegstein
    •  & Michael C. Oldham

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Contributions

M.C.O. conceived the GCASS strategy and J.H.L generated the GCASS data set. A.J. generated the FACS mRG data set. M.C.O. conceived, designed and performed the bioinformatic analyses. J.H.L., T.J.N. and A.A.P. designed and performed the experiments leading up to the prioritization of PDGFD as the focus of this study. T.J.N. performed the majority of the in situ hybridizations and the in vivo mouse experiments. J.H.L. performed the human and mouse slice culture experiments, as well as all of the immunostaining, imaging and image analysis in the study. M.C.O. and J.H.L. wrote the manuscript, which was edited by all the authors. M.C.O. and A.R.K provided conceptual guidance at every stage of the project.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Arnold R. Kriegstein or Michael C. Oldham.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Text and Data, Supplementary Figures 1-4, Supplementary Table 1 and additional references (see Contents page for details).

Excel files

  1. 1.

    Supplementary Table 1

    This file shows sample characteristics of the GCASS dataset.

  2. 2.

    Supplementary Table 2

    The file shows genes expressed significantly higher in E14 mouse neocortical RG vs. IPC (the FACS-mRG dataset).

  3. 3.

    Supplementary Table 3

    This file contains a summary of predicted RG expression specificity, mean expression levels, and associated information for all genes and all datasets.

  4. 4.

    Supplementary Table 4

    This file contains results of enrichment analyses for conserved and species-specific RG-expressed genes depicted in Fig. 2a, d.

About this article

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DOI

https://doi.org/10.1038/nature13973

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