REV-ERBα mediates complement expression and diurnal regulation of microglial synaptic phagocytosis
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...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2020-12-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/58765 |
| _version_ | 1811200215749754880 |
|---|---|
| author | Percy Griffin Patrick W Sheehan Julie M Dimitry Chun Guo Michael F Kanan Jiyeon Lee Jinsong Zhang Erik S Musiek |
| author_facet | Percy Griffin Patrick W Sheehan Julie M Dimitry Chun Guo Michael F Kanan Jiyeon Lee Jinsong Zhang Erik S Musiek |
| author_sort | Percy Griffin |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T02:00:58Z |
| format | Article |
| id | doaj.art-0ab574e86a24483f961650ad5eafeaa9 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:00:58Z |
| publishDate | 2020-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-0ab574e86a24483f961650ad5eafeaa92022-12-22T03:52:40ZengeLife Sciences Publications LtdeLife2050-084X2020-12-01910.7554/eLife.58765REV-ERBα mediates complement expression and diurnal regulation of microglial synaptic phagocytosisPercy Griffin0Patrick W Sheehan1Julie M Dimitry2Chun Guo3Michael F Kanan4Jiyeon Lee5Jinsong Zhang6Erik S Musiek7https://orcid.org/0000-0002-8873-0360Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, United StatesDepartment of Neurology, Washington University School of Medicine in St. Louis, St. Louis, United StatesDepartment of Neurology, Washington University School of Medicine in St. Louis, St. Louis, United StatesDepartment of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, United StatesDepartment of Neurology, Washington University School of Medicine in St. Louis, St. Louis, United StatesDepartment of Neurology, Washington University School of Medicine in St. Louis, St. Louis, United StatesDepartment of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, United StatesDepartment of Neurology, Washington University School of Medicine in St. Louis, St. Louis, United States; Hope Center for Neurological Disorders, Washington University School of Medicine in St. Louis, St. Louis, United StatesThe 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.https://elifesciences.org/articles/58765circadian rhythmsynaptic terminalscomplementneuron-glia interactions |
| spellingShingle | Percy Griffin Patrick W Sheehan Julie M Dimitry Chun Guo Michael F Kanan Jiyeon Lee Jinsong Zhang Erik S Musiek REV-ERBα mediates complement expression and diurnal regulation of microglial synaptic phagocytosis eLife circadian rhythm synaptic terminals complement neuron-glia interactions |
| title | REV-ERBα mediates complement expression and diurnal regulation of microglial synaptic phagocytosis |
| title_full | REV-ERBα mediates complement expression and diurnal regulation of microglial synaptic phagocytosis |
| title_fullStr | REV-ERBα mediates complement expression and diurnal regulation of microglial synaptic phagocytosis |
| title_full_unstemmed | REV-ERBα mediates complement expression and diurnal regulation of microglial synaptic phagocytosis |
| title_short | REV-ERBα mediates complement expression and diurnal regulation of microglial synaptic phagocytosis |
| title_sort | rev erbα mediates complement expression and diurnal regulation of microglial synaptic phagocytosis |
| topic | circadian rhythm synaptic terminals complement neuron-glia interactions |
| url | https://elifesciences.org/articles/58765 |
| work_keys_str_mv | AT percygriffin reverbamediatescomplementexpressionanddiurnalregulationofmicroglialsynapticphagocytosis AT patrickwsheehan reverbamediatescomplementexpressionanddiurnalregulationofmicroglialsynapticphagocytosis AT juliemdimitry reverbamediatescomplementexpressionanddiurnalregulationofmicroglialsynapticphagocytosis AT chunguo reverbamediatescomplementexpressionanddiurnalregulationofmicroglialsynapticphagocytosis AT michaelfkanan reverbamediatescomplementexpressionanddiurnalregulationofmicroglialsynapticphagocytosis AT jiyeonlee reverbamediatescomplementexpressionanddiurnalregulationofmicroglialsynapticphagocytosis AT jinsongzhang reverbamediatescomplementexpressionanddiurnalregulationofmicroglialsynapticphagocytosis AT eriksmusiek reverbamediatescomplementexpressionanddiurnalregulationofmicroglialsynapticphagocytosis |