Endogenous circadian clock machinery in cortical NG2-glia regulates cellular proliferation

Abstract

The molecular circadian clock can be found throughout the body and is essential for the synchronizing cellular physiology with the 24-hour day. However, the role of the clock in regulating the brain’s regenerative potential has not been explored. We report here that murine NG2-glia, the largest population of proliferative cells in the mature central nervous system, rhythmically express circadian clock genes in a 24-hour period, including the critical clock component Bmal1 RNA and BMAL1 protein. Interestingly, daily NG2-glia proliferation preferentially occurs during the time of day in which Bmal1 expression is high, while conditional knockout (CKO) of Bmal1 decreases both cortical NG2-glia density and cellular proliferation. Furthermore, in a neurotrauma model, we show that pathology-induced NG2-glia proliferation is also dependent on Bmal1 expression. Because circadian rhythm disturbances are common in neurologic disorders across the lifespan, including in TBI, these findings bear significant implications for cellular regeneration in brain injuries and disease.

SIGNIFICANCE STATEMENT

Circadian rhythm disturbances are commonly seen in neurologic disorders across the lifespan. The ramifications of these disturbances for the brain’s cellular healing capabilities are unknown. We show here that the largest population of regenerative cells in the adult central nervous system, known as NG2-glia, are indeed dependent upon the integrity of their endogenous circadian rhythms. They not only rhythmically express molecular clock components, but the critical clock gene Bmal1 plays an important role in regulating their ability to proliferate, both at rest and after injury. These findings underscore the importance of circadian dysregulation in affecting brain recovery at the cellular level in neurologic disease.