BMAL1 loss in oligodendroglial lineage cells dysregulates myelination and sleep

Abstract

Myelination depends on maintenance of oligodendrocytes that arise from oligodendrocyte precursor cells (OPCs). We show that the dynamic nature of oligodendroglia and myelination are regulated by the circadian transcription factor BMAL1. Bmal1 knockdown in OPCs during development – but not adulthood – decreases OPC proliferation, whereas BMAL1 regulates OPC morphology throughout life. OPC-specific Bmal1 deficiency impairs remyelination in an age-dependent manner, suggesting that age-associated decrements in circadian regulation of oligodendroglia may contribute to the deficient remyelination potential in demyelinating diseases like multiple sclerosis (MS). This oligodendroglial dysregulation and dysmyelination increase sleep fragmentation in OPC-specific Bmal1 knockout mice, and sleep fragmentation is causally associated with MS. These findings have broad mechanistic and therapeutic implications for numerous brain disorders that include both myelin and sleep phenotypes.One-Sentence SummaryBMAL1 regulates the homeostatic maintenance of oligodendroglia and myelin, that subsequently controls sleep architecture.

Circadian Control of Glial Cell Homeodynamics

“…Notwithstanding the known importance of myelination in system-wide neural circuit function, the intrinsic circadian clock control of OPCs, myelin-forming cells, and myelination is quite understudied compared with the circadian regulation of astrocytes and microglia. To date, numerous components of the transcriptional molecular clock have been identified throughout the oligodendroglial lineage in both mice and humans (Zhang Y, et al, 2014(Zhang Y, et al, , 2016Rojo et al, 2022), which has been confirmed at the proteomic level with PER2 staining in oligodendrocytes (Colwell and Ghiani, 2020) and BMAL1 staining in OPCs (Rojo et al, 2022). In addition, isolated OPCs show rhythmic expression of Bmal1, Per2, and Rev-Erbα that is disrupted by the lack of Bmal1 (Rojo et al, 2022).…”

“…To date, numerous components of the transcriptional molecular clock have been identified throughout the oligodendroglial lineage in both mice and humans (Zhang Y, et al, 2014(Zhang Y, et al, , 2016Rojo et al, 2022), which has been confirmed at the proteomic level with PER2 staining in oligodendrocytes (Colwell and Ghiani, 2020) and BMAL1 staining in OPCs (Rojo et al, 2022). In addition, isolated OPCs show rhythmic expression of Bmal1, Per2, and Rev-Erbα that is disrupted by the lack of Bmal1 (Rojo et al, 2022).…”

“…CLOCK: BMAL1 also modulates the expression of REV-ERB (cyan) and ROR (green), that bind to RORE elements (purple) and inhibit or induce BMAL1, respectively. A complete intrinsic molecular clock is present in oligodendroglia with rhythmic levels of expression across the circadian day (Zhang Y, et al, 2014; Rojo et al, 2022). In mice, the level of expression of genes that control OPC proliferation and differentiation, myelination, and oligodendroglia apoptosis vary between the rest and wake phases (Bellesi et al, 2013).…”

“…One of the main OPC proliferation regulators, Sox5, is controlled by BMAL1 and its disruption leads to decreased Sox5 expression during the light phase (Rojo et al, 2022). Consequently, the disruption of the clock leads to a decrease in OPC proliferation and density and myelination (Rojo et al, 2022). Collectively, this daily variation points toward evidence of circadian-mediated oligodendroglial density maintenance.…”

“…However, it contradicts previous evidence found in humans (Lavtar et al, 2018) as it suggests that Bmal1 depletion could be beneficial in a demyelinating lesion. Given the recent findings that the molecular clock in oligodendroglia influences homeostasis and remyelination (Rojo et al, 2022), it is intriguing to speculate that the high prevalence of demyelinating disorders with increased latitude (Simpson et al, 2019) and in night shift workers (Hedström et al, 2011) could be related to changes in the interactions between circadian and myelin biology. One of the many changes that accompany geographic latitudes approaching the poles is variations in the light-dark cycle with substantial portions of the year experiencing light cycles ranging from continual light to continual darkness, 2 environmental states known to cause dysregulation in the circadian system.…”