The circadian clock is a pacemaker of the axonal regenerative ability

De Virgiliis, F.; Mueller, F.; Palmisano, I.; Chadwick, J. S.; Luengo Gutierrez, L.; Giarrizzo, A.; Yan, Y.; Danzi, M. C.; Picon Munoz, C.; Zhou, L.; Kong, G.; Serger, E.; Hutson, T. H.; Scheiermann, C.; Brancaccio, M.; Di Giovanni, S.

doi:10.1101/2023.08.07.552230

bioRxiv · 10.1101/2023.08.07.552230

The circadian clock is a pacemaker of the axonal regenerative ability

De Virgiliis, F.·Mueller, F.·Palmisano, I.·Chadwick, J. S.·Luengo Gutierrez, L.·Giarrizzo, A.·Yan, Y.·Danzi, M. C.·Picon Munoz, C.·Zhou, L.·Kong, G.·Serger, E.·Hutson, T. H.·Scheiermann, C.·Brancaccio, M.·Di Giovanni, S.

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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.

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De Virgiliis, F., Mueller, F., Palmisano, I., Chadwick, J. S., Luengo Gutierrez, L., Giarrizzo, A., Yan, Y., Danzi, M. C., Picon Munoz, C., Zhou, L., Kong, G., Serger, E., Hutson, T. H., Scheiermann, C., Brancaccio, M., Di Giovanni, S.. 2023-08-07. The circadian clock is a pacemaker of the axonal regenerative ability. https://doi.org/10.1101/2023.08.07.552230

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