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Cited by 73Neuroinflammation and Neurodegeneration MechanismsCircadian rhythm and melatoninNeuroscience and Neuropharmacology Research

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

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Griffin, Percy, Sheehan, Patrick W, Dimitry, Julie M, Guo, Chun, Kanan, Michael F, Lee, Jiyeon, Zhang, Jinsong, Musiek, Erik S·2020·eLife
DOI 10.7554/elife.58765PMC PMC7728439

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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-ERBα, and deletion of REV-ERBα causes increased expression of C4b transcript in neurons and astrocytes as well as C3 protein primarily in astrocytes. REV-ERBα 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-ERBα axis as a regulator of complement expression and synaptic phagocytosis in the brain, linking circadian proteins to synaptic regulation.

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  • BMAL1 may affect glial cell activation and neurodegeneration through REV-ERBα.

    “Further studies suggested that BMAL1 may affect glial cells activation and neurodegeneration through REV-ERBα, which is a nuclear receptor as well as a circadian clock component that can be induced by BMAL1.123–125”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [123]

    The Results and Discussion link BMAL1 loss to reduced REV-ERBα expression and describe REV-ERBα-dependent complement changes, glial activation, and synapse loss. The Discussion says these findings have implications for neurodegenerative disease, but also reports no overt neurodegenerative response in the mice studied. Thus the proposed pathway is supported, while an effect on neurodegeneration itself remains unshown. (LLM, conf=0.82)

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Cited by

Sorted by citations

Authors
Griffin, P., Sheehan, P. W., Dimitry, J. M., Guo, C., Kanan, M. F., Lee, J., Zhang, J., & Musiek, E. S.
Affiliations
  • Washington University in St. Louis (US)
  • Saint Louis University (US)
Corresponding author
Musiek, Erik S
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2020-12-01
Volume
9
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.58765
PMC
PMC7728439
OpenAlex
W3108832777
Cited by
73
References
9
Citations by year
2026: 9 · 2025: 12 · 2024: 14 · 2023: 14 · 2022: 15 · 2021: 8 · 2020: 1
FWCI
3.68
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institute on Aging (R01AG054517, R01AG063743)
  • Cure Alzheimer's Fund (Investigator award)
  • Coins for Alzheimer's Research Trust (Investigator award)
  • National Science Foundation (DGE- 1745038)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
NR1D1, Bmal1, circadian clock, complement system, C4b, complement C3, synaptic loss, diurnal variation, hippocampus, astrocytes, neurons, CA3
MeSH terms
Animals, Cells, Cultured, Circadian Rhythm, Complement System Proteins, Complement C3, Complement C4, Female, Male, Mice, Inbred C57BL, Phagocytosis, Synapses, Time Factors, Signal Transduction, Up-Regulation, Microglia, Mice, Knockout, CA3 Region, Hippocampal, ARNTL Transcription Factors, Nuclear Receptor Subfamily 1, Group D, Member 1

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