Demyelination Regulates the Circadian Transcription Factor BMAL1 to Signal Adult Neural Stem Cells to Initiate Oligodendrogenesis

Abstract

Circadian clocks are endogenous oscillators that generate cell-autonomous rhythms that govern cellular processes and are synchronized by external cues in the local macro- and micro-environments. Demyelination, a common brain pathology with variable degrees of recovery, changes the microenvironment via damaged myelin and activation of glial cells. How these microenvironmental changes affect local circadian clocks and with what consequences is mostly unknown. Here, we show that within demyelinating lesions, astrocyte circadian clocks produce the Wnt inhibitors SFRP1 and SFRP5. Unexpectedly, SFRP1 and SFRP5 signal to the subventricular zone (SVZ) to reduce the circadian transcription factor BMAL1. This sequence of events causes adult neural stem cells in the SVZ to differentiate into oligodendrocyte lineage cells, which are then supplied to demyelinated lesions. Our findings show that circadian clocks in demyelinating lesions respond to microenvironmental changes and communicate with the SVZ to enhance a natural repair system of spontaneous remyelination.