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The circadian clock time tunes axonal regeneration

De Virgiliis, F;Mueller, F;Palmisano, I;Chadwick, JS;Luengo-Gutierrez, L;Giarrizzo, A;Yan, Y;Danzi, MC;Picon-Muñoz, C;Zhou, L;Kong, G;Serger, E;Hutson, TH;Maldonado-Lasuncion, I;Song, Y;Scheiermann, C;Brancaccio, M;Di Giovanni, S;

Nerve injuries cause permanent neurological disability due to limited axonal regeneration. Injury-dependent and -independent mechanisms have provided important insight into neuronal regeneration, however, common denominators underpinning regeneration remain elusive. A comparative analysis of transcriptomic datasets associated with neuronal regenerative ability revealed circadian rhythms as the most significantly enriched pathway. Subsequently, we demonstrated that sensory neurons possess an endogenous clock and that their regenerative ability displays diurnal oscillations in a murine model of sciatic nerve injury. Consistently, transcriptomic analysis showed a time-of-day-dependent enrichment for processes associated with axonal regeneration and the circadian clock. Conditional deletion experiments demonstrated that Bmal1 is required for neuronal intrinsic circadian regeneration and target re-innervation. Lastly, lithium enhanced nerve regeneration in wild-type but not in clock-deficient mice. Together, these findings demonstrate that the molecular clock fine-tunes the regenerative ability of sensory neurons and propose compounds affecting clock pathways as a novel approach to nerve repair.