The circadian clock is a pacemaker of the axonal regenerative ability

Abstract

Peripheral nervous system injuries lead to long-term neurological disability due to limited axonal regenerative ability. Injury-dependent and -independent physiological mechanisms have provided important molecular insight into neuronal regeneration. However, whether common molecular denominators underpin both injury-dependent and independent biological processes remain unclear. Here, we performed a comparative analysis of recently generated transcriptomic datasets associated with the regenerative ability of sciatic dorsal root ganglia (DRG). Surprisingly, circadian rhythms were identified as a the most significantly enriched biological process associated with regenerative capability. We demonstrate that DRG neurons possess an endogenous circadian clock with a 24h oscillations of circadian genes and that their regenerative ability displays a diurnal oscillation in a mouse model of sciatic nerve injury. Consistently, transcriptomic analysis of DRG neurons showed a significant time-of-day dependent enrichment for processes associated with axonal regeneration, development and growth, as well as circadian associated genes, including the core clock genes Bmal1 and Clock. Indeed, DRG-specific ablation of the non-redundant clock gene Bmal1 showed that it is required for regenerative gene expression, neuronal intrinsic circadian regeneration and target reinnervation. Lastly, lithium, a chrono-active compound, enhanced nerve regeneration, in wildtype but not in Bmal1 and Cry1/2-deficient mice. Together, these data demonstrate that daily rhythms and the molecular clock fine-tune the regenerative response of DRG neurons, and that chrono-active drugs, such as lithium, are a novel potential approach to nerve repair.