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. 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.