REV-ERBα mediates complement expression and diurnal regulation of microglial synaptic phagocytosis
- Washington University School of Medicine in St. Louis, United States
- 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.
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REV-ERBα mediates complement expression and circadian regulation of microglial synaptic phagocytosisDryad Digital Repository, doi:10.5061/dryad.nzs7h44p1.
Article and author information
Author details
Erik Steven Musiek
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.
Reviewing Editor
- Louis J Ptáček, University of California, San Francisco, United States
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).
Version history
- Received: May 10, 2020
- Accepted: November 27, 2020
- Accepted Manuscript published: December 1, 2020 (version 1)
- 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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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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