Department of Life Sciences, Korea University, 02841 Seoul, Republic of Korea.
Department of Molecular Neuroscience, Dong-A University College of Medicine, 49201 Busan, Republic of Korea.
Proc Natl Acad Sci U S A. 2020 Jul 7;117(27):15955-15966. doi: 10.1073/pnas.1920829117. Epub 2020 Jun 17.
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 , which encodes the stem cell marker prominin-1, as a regulator of the axon regeneration program. expression is developmentally down-regulated, and the genetic deletion of in mice inhibits axon regeneration in dorsal root ganglion (DRG) cultures and in the sciatic nerve, revealing the neuronal role of 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. 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 and cholesterol metabolism pathways are possible therapeutic targets for the promotion of neural recovery after injury.
轴突再生受神经元内在转录程序调控，该程序在发育过程中受到抑制，但在周围神经损伤后可以被重新激活。在这里，我们确定 ，它编码干细胞标记物 prominin-1，是轴突再生程序的调节剂。 表达在发育过程中被下调，并且在小鼠中缺失 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 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在体外和体内培养的 DRG 神经元或小鼠中升高 prominin-1 水平，可增强轴突再生，从而允许在抑制性基质上生长。 过表达以 Smad 途径依赖的方式诱导胆固醇代谢相关基因的一致下调和细胞胆固醇水平降低，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 的磷酸化。这些结果表明 和胆固醇代谢途径可能是促进损伤后神经恢复的治疗靶点。
