Article | Published:

Developmental diversification of cortical inhibitory interneurons

Nature volume 555, pages 457462 (22 March 2018) | Download Citation

Abstract

Diverse subsets of cortical interneurons have vital roles in higher-order brain functions. To investigate how this diversity is generated, here we used single-cell RNA sequencing to profile the transcriptomes of mouse cells collected along a developmental time course. Heterogeneity within mitotic progenitors in the ganglionic eminences is driven by a highly conserved maturation trajectory, alongside eminence-specific transcription factor expression that seeds the emergence of later diversity. Upon becoming postmitotic, progenitors diverge and differentiate into transcriptionally distinct states, including an interneuron precursor state. By integrating datasets across developmental time points, we identified shared sources of transcriptomic heterogeneity between adult interneurons and their precursors, and uncovered the embryonic emergence of cardinal interneuron subtypes. Our analysis revealed that the transcription factor Mef2c, which is linked to various neuropsychiatric and neurodevelopmental disorders, delineates early precursors of parvalbumin-expressing neurons, and is essential for their development. These findings shed new light on the molecular diversification of early inhibitory precursors, and identify gene modules that may influence the specification of human interneuron subtypes.

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Acknowledgements

We thank members of the Fishell and Satija laboratories, and C. Desplan, for feedback and discussion; L. Harshman, B. Bracken and W. Stephenson for assistance with scRNA-seq experiments; and N. Habib for assistance with published datasets. This work was supported by National Institutes of Health (NIH) grants R01 NS074972 (G.F.), R01 NS081297 (G.F.), MH071679-12 (G.F. and R.S.), NIH DP2-HG-009623 (R.S.), European Molecular Biology Organization ALTF 1295-2012 (C.M.), Deutsche Forschungsgemeinschaft Postdoctoral Fellow (C.H.), NIH F30MH114462 (R.C.B.), T32GM007308 (R.C.B.), NIH F31NS103398 (K.A.), and National Science Foundation DGE1342536 (A.B.). G.F. is also supported by a grant from the Simons Foundation (274578).

Author information

Author notes

    • Christian Mayer
    • , Christoph Hafemeister
    •  & Rachel C. Bandler

    These authors contributed equally to this work.

Affiliations

  1. NYU Neuroscience Institute, Langone Medical Center, New York, New York 10016, USA

    • Christian Mayer
    • , Rachel C. Bandler
    • , Robert Machold
    • , Renata Batista Brito
    • , Xavier Jaglin
    • , Kathryn Allaway
    •  & Gord Fishell
  2. New York Genome Center, New York, New York 10013, USA.

    • Christian Mayer
    • , Christoph Hafemeister
    • , Andrew Butler
    •  & Rahul Satija
  3. Harvard Medical School, Department of Neurobiology, Boston, Massachusetts 02115, USA

    • Christian Mayer
    • , Xavier Jaglin
    • , Kathryn Allaway
    •  & Gord Fishell
  4. Broad Institute, Stanley Center for Psychiatric Research, Cambridge, Massachusetts 02142, USA

    • Christian Mayer
    •  & Gord Fishell
  5. Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA

    • Renata Batista Brito
  6. Center for Genomics and Systems Biology, New York University, New York, New York 10012, USA

    • Andrew Butler
    •  & Rahul Satija
  7. Center for Genomics and Systems Biology, New York University, PO Box 129188, Saadiyat Island, Abu Dhabi, United Arab Emirates

    • Gord Fishell

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Contributions

C.M., C.H., R.C.B., G.F. and R.S. conceived the research. C.M. and R.C.B. led experimental work, assisted by R.M., R.B.B., X.J., K.A. and supervised by G.F. C.H. led computational analysis, assisted by C.M. and A.B., and supervised by R.S. All authors participated in interpretation and writing the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Gord Fishell or Rahul Satija.

Reviewer Information Nature thanks A. Klein and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

PDF files

  1. 1.

    Life Sciences Reporting Summary

Excel files

  1. 1.

    Supplementary Table 1

    This file contains a summary of scRNA-seq experiments.

  2. 2.

    Supplementary Table 2

    This file contains differentially expressed TFs across eminences within mitotic cells.

  3. 3.

    Supplementary Table 3

    This file contains temporally regulated genes in mitotic GE cells and and their MT bin of maximal expression.

  4. 4.

    Supplementary Table 4

    This file contains differentially expressed genes between postmitotic branches.

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DOI

https://doi.org/10.1038/nature25999

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