The circadian clock is a pacemaker of the axonal regenerative ability
Authored by
Francesco De Virgiliis, Franziska Mueller, Ilaria Palmisano, Jessica S Chadwick, Lucía Luengo Gutierrez, Angela Giarrizzo, Yuyang Yan, Matt Christopher Danzi, Carmen Picón Muñoz, Luming Zhou, Guiping Kong, Elisabeth Serger, Thomas Haynes Hutson, ines Maldonado, Yayue Song, Christoph Scheiermann, Marco Brancaccio, and Simone Di Giovanni
Posted
August 7, 2023
Server
bioRxiv
Summary 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 genesBmal1 andClock . Indeed, DRG-specific ablation of the non-redundant clock geneBmal1 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 inBmal1 andCry1/2 -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.
