TFEB and TFE3 (TFEB/3), key regulators of lysosomal biogenesis and autophagy, play diverse roles depending on cell type. This study highlights a hitherto unrecognized role of TFEB/3 crucial for peripheral nerve repair. Specifically, they promote the generation of progenitor-like repair Schwann cells after axonal injury. In Schwann cell-specific TFEB/3 double knock-out mice of either sex, the TFEB/3 loss disrupts the transcriptomic reprogramming that is essential for the formation of repair Schwann cells. Consequently, mutant mice fail to populate the injured nerve with repair Schwann cells and exhibit defects in axon regrowth, target reinnervation, and functional recovery. TFEB/3 deficiency inhibits the expression of injury-responsive repair Schwann cell genes, despite the continued expression of c-jun, a previously identified regulator of repair Schwann cell function. TFEB/3 binding motifs are enriched in the enhancer regions of injury-responsive genes, suggesting their role in repair gene activation. Autophagy-dependent myelin breakdown is not impaired despite TFEB/3 deficiency. These findings underscore a unique role of TFEB/3 in adult Schwann cells that is required for proper peripheral nerve regeneration.

TFEB 和 TFE3 (TFEB/3) 是溶酶体生物发生和自噬的关键调节因子，根据细胞类型发挥不同的作用。这项研究强调了 TFEB/3 对周围神经修复至关重要的迄今为止未被认识的作用。具体来说，它们促进轴突损伤后类祖细胞修复雪旺细胞的产生。在施万细胞特异性 TFEB/3 双敲除小鼠中，无论性别，TFEB/3 缺失都会破坏转录组重编程，而转录组重编程对于修复施万细胞的形成至关重要。因此，突变小鼠无法用修复雪旺细胞填充受损神经，并在轴突再生、目标神经支配和功能恢复方面表现出缺陷。 TFEB/3 缺陷会抑制损伤反应性修复施万细胞基因的表达，尽管 c -jun （先前确定的修复施万细胞功能的调节因子）持续表达。 TFEB/3 结合基序在损伤反应基因的增强子区域富集，表明它们在修复基因激活中的作用。尽管 TFEB/3 缺乏，但自噬依赖性髓磷脂分解并未受损。这些发现强调了 TFEB/3 在成体雪旺细胞中的独特作用，这是适当的周围神经再生所必需的。