REV-ERBα mediates complement expression and diurnal regulation of microglial synaptic phagocytosis
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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.
Keywords: circadian rhythm; complement; mouse; neuron-glia interactions; neuroscience; synaptic
terminals.
Reference
Griffin, P., Sheehan, P. W., Dimitry, J. M., Guo, C., Kanan, M. F., Lee, J., ... & Musiek, E. S. (2020). REV-ERBα mediates complement expression and diurnal regulation of microglial synaptic phagocytosis. Elife, 9, e58765.
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