REV-ERBα mediates complement expression and diurnal regulation of microglial synaptic phagocytosis

  1. Percy Griffin
  2. Patrick W Sheehan
  3. Julie M Dimitry
  4. Chun Guo
  5. Michael F Kanan
  6. Jiyeon Lee
  7. Jinsong Zhang
  8. Erik Steven Musiek  Is a corresponding author
  1. Washington University School of Medicine in St. Louis, United States
  2. Saint Louis University School of Medicine, United States

Abstract

The circadian clock regulates various aspects of brain health including microglial and astrocyte activation. Here we report that deletion of the master clock protein BMAL1 in mice robustly increases expression of complement genes, including C4b and C3, in the hippocampus. BMAL1 regulates expression of the transcriptional repressor REV-ERBa, and deletion of REV-ERBa causes increased expression of C4b transcript in neurons and astrocytes as well as C3 protein primarily in astrocytes. REV-ERBa deletion increased microglial phagocytosis of synapses and synapse loss in the CA3 region of the hippocampus. Finally, we observed diurnal variation in the degree of microglial synaptic phagocytosis which was antiphase to REV-ERBα expression. This daily variation in microglial synaptic phagocytosis was abrogated by global REV-ERBα deletion, which caused persistently elevated synaptic phagocytosis. This work uncovers the BMAL1-REV-ERBa axis as a regulator of complement expression and synaptic phagocytosis in the brain, linking circadian proteins to synaptic regulation.

Data availability

The microarray data used in Fig. 1 is available on ArrayExpress E-MTAB-7590 and E-MTAB-7151.We have also uploaded all of the raw data from all of the figures in the paper as Source Files and to Dryad, which is available at: https://doi.org/10.5061/dryad.nzs7h44p1.This includes all of the image quantification data. Raw image files were not uploaded, as there are several hundred and they exceed 20GB.

The following previously published data sets were used

Article and author information

Author details

  1. Percy Griffin

    Neurology, Washington University School of Medicine in St. Louis, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Patrick W Sheehan

    Neurology, Washington University School of Medicine in St. Louis, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Julie M Dimitry

    Neurology, Washington University School of Medicine in St. Louis, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Chun Guo

    Pharmacology and Physiological Sciences, Saint Louis University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Michael F Kanan

    Neurology, Washington University School of Medicine in St. Louis, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jiyeon Lee

    Neurology, Washington University School of Medicine in St. Louis, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jinsong Zhang

    Pharmacology and Physiological Sciences, Saint Louis University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Erik Steven Musiek

    Neurology, Washington University School of Medicine in St. Louis, St. Louis, United States
    For correspondence
    musieke@wustl.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8873-0360

Funding

National Institute on Aging (R01AG054517)

  • Erik Steven Musiek

National Institute on Aging (R01AG063743)

  • Erik Steven Musiek

Cure Alzheimer's Fund (Investigator award)

  • Erik Steven Musiek

Coins for Alzheimer's Research Trust (Investigator award)

  • Erik Steven Musiek

National Science Foundation (DGE- 1745038)

  • Percy Griffin

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments were conducted in accordance with recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health, and were approved by the institutional animal care and use committee (IACUC) at Washington University under protocol 2017-0124 (E. Musiek, PI).

Reviewing Editor

  1. Louis J Ptáček, University of California, San Francisco, United States

Publication history

  1. Received: May 10, 2020
  2. Accepted: November 27, 2020
  3. Accepted Manuscript published: December 1, 2020 (version 1)
  4. Version of Record published: December 10, 2020 (version 2)

Copyright

© 2020, Griffin et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Percy Griffin
  2. Patrick W Sheehan
  3. Julie M Dimitry
  4. Chun Guo
  5. Michael F Kanan
  6. Jiyeon Lee
  7. Jinsong Zhang
  8. Erik Steven Musiek
(2020)
REV-ERBα mediates complement expression and diurnal regulation of microglial synaptic phagocytosis
eLife 9:e58765.
https://doi.org/10.7554/eLife.58765

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