Axon regeneration is regulated by a neuron-intrinsic transcriptional program that is suppressed during development but that can be reactivated following peripheral nerve injury. Here we identify Prom1, which encodes the stem cell marker prominin-1, as a regulator of the axon regeneration program. Prom1 expression is developmentally down-regulated, and the genetic deletion of Prom1 in mice inhibits axon regeneration in dorsal root ganglion (DRG) cultures and in the sciatic nerve, revealing the neuronal role of Prom1 in injury-induced regeneration. Elevating prominin-1 levels in cultured DRG neurons or in mice via adeno-associated virus-mediated gene delivery enhances axon regeneration in vitro and in vivo, allowing outgrowth on an inhibitory substrate. Prom1 overexpression induces the consistent down-regulation of cholesterol metabolism-associated genes and a reduction in cellular cholesterol levels in a Smad pathway-dependent manner, which promotes axonal regrowth. We find that prominin-1 interacts with the type I TGF-β receptor ALK4, and that they synergistically induce phosphorylation of Smad2. These results suggest that Prom1 and cholesterol metabolism pathways are possible therapeutic targets for the promotion of neural recovery after injury.

轴突再生受到神经元固有转录程序的调节，该程序在发育过程中受到抑制，但在周围神经损伤后可以重新激活。在这里，我们鉴定出Prom1 ，它编码干细胞标记 prominin-1，作为轴突再生程序的调节剂。 Prom1表达在发育过程中下调，小鼠中Prom1的基因缺失会抑制背根神经节 (DRG) 培养物和坐骨神经中的轴突再生，揭示了Prom1在损伤诱导的再生中的神经元作用。通过腺相关病毒介导的基因传递提高培养的 DRG 神经元或小鼠中的 prominin-1 水平，可增强轴突在体外和体内的再生，从而允许在抑制性底物上生长。 Prom1过表达会诱导胆固醇代谢相关基因持续下调，并以 Smad 通路依赖性方式降低细胞胆固醇水平，从而促进轴突再生。我们发现 prominin-1 与 I 型 TGF-β 受体 ALK4 相互作用，并且它们协同诱导 Smad2 磷酸化。这些结果表明Prom1和胆固醇代谢途径是促进损伤后神经恢复的可能治疗靶点。