TFEB/3 govern repair Schwann cell generation and function following peripheral nerve injury

After peripheral nerve injury, adult Schwann cells convert to progenitor cell-like repair Schwann cells, which are pivotal for nerve regeneration. We show that Schwann cell-specific deletion of TFEB/3 disrupts the transcriptomic reprogramming necessary for injury-induced repair Schwann cell generation in mice. The mutant mice fail to generate proliferating repair Schwann cells to populate the injured nerves. Distal Schwann cells fail to express injury-responsive genes and continue to maintain the expression of myelin-associated genes. TFEB/3 binding motifs are enriched in injury-induced enhancers, suggesting their role in repair gene activation. Autophagy-dependent myelin breakdown is not impaired in the mutant mice despite the known function of TFEB/3 as autophagy activators. However, the mutant mice exhibit defects in axon regeneration, target reinnervation, and functional recovery. Therefore, TFEB/3 play a critical role in orchestrating transcriptional changes essential for repair Schwann cell generation and function necessary for peripheral nerve regeneration. Overall design: To investigate the role of TFEB and TFE3 in the generation of repair Schwann cells after sciatic nerve injury we developed Tfeb/3 SC-dKO mice with a Schwann cell specific Dhh-Cre driven Tfeb knockout on a global Tfe3 knockout background (Dhh-Cre+:Tfebflox/flox;Tfe3KO) and control mice (Dhh-Cre-:Tfebflox/flox;Tfe3+). Intact sciatic nerves without nerve injury and distal segments following 5 days post transection injury (5DPI) were examined by RNA-seq analysis. Transcriptomic analysis was performed with 4 groups: Control Intact (100), Tfeb/3 SC-dKO Intact (200), Control 5DPI (300), and Tfeb/3 SC-dKO 5DPI (400), with 3 biological replicates per group.