Department of Anesthesia, Division of Pain Management, Cincinnati Children's Hospital Medical Center, United States; Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, OH 45229, United States; Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, United States.
Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, United States.
Neuroscience. 2018 Jul 1;382:93-104. doi: 10.1016/j.neuroscience.2018.04.037. Epub 2018 May 8.
The peripherally projecting axons of dorsal root ganglion (DRG) neurons readily regenerate after damage while their centrally projecting branches do not regenerate to the same degree after injury. One important reason for this inconsistency is the lack of pro-regeneration gene expression that occurs in DRG neurons after central injury relative to peripheral damage. The transcription factor SRY-box-containing gene 11 (Sox11) may be a crucial player in the regenerative capacity of axons as previous evidence has shown that it is highly upregulated after peripheral axon damage but not after central injury. Studies have also shown that overexpression or inhibition of Sox11 after peripheral nerve damage can promote or block axon regeneration, respectively. To further understand the mechanisms of how Sox11 regulates axon growth, we artificially overexpressed Sox11 in DRG neurons in vitro to determine if increased levels of this transcription factor could enhance neurite growth. We found that Sox11 overexpression significantly enhanced neurite branching in vitro, and specifically induced the expression of glial cell line-derived neurotrophic factor (GDNF) family receptors, GFRα1 and GFRα3. The upregulation of these receptors by Sox11 overproduction altered the neurite growth patterns of DRG neurons alone and in response to growth factors GDNF and artemin; ligands for GFRα1 and GFRα3, respectively. These data support the role of Sox11 to promote neurite growth by altering responsiveness of neurotrophic factors and may provide mechanistic insight as to why peripheral axons of sensory neurons readily regenerate after injury, but the central projections do not have an extensive regenerative capacity.
背根神经节 (DRG) 神经元的外周投射轴突在损伤后很容易再生，而其向中枢投射的分支在损伤后则不能再生到相同程度。造成这种不一致的一个重要原因是，相对于外周损伤，DRG 神经元在中枢损伤后缺乏促再生基因表达。转录因子 SRY 盒基因 11（Sox11）可能是轴突再生能力的关键因素，因为先前的证据表明，它在外周轴突损伤后高度上调，但在中枢损伤后则没有。研究还表明，外周神经损伤后 Sox11 的过表达或抑制分别可以促进或阻断轴突再生。为了进一步了解 Sox11 调节轴突生长的机制，我们在体外人工过表达 Sox11 于 DRG 神经元中，以确定这种转录因子水平的增加是否可以增强轴突生长。我们发现 Sox11 的过表达显著增强了体外轴突分支，并且特异性诱导了神经胶质细胞系衍生的神经营养因子 (GDNF) 家族受体，GFRα1 和 GFRα3 的表达。Sox11 过表达引起这些受体的上调改变了 DRG 神经元的轴突生长模式，并且单独和响应神经营养因子 GDNF 和 artemin 而改变；分别为 GFRα1 和 GFRα3 的配体。这些数据支持 Sox11 通过改变神经营养因子的反应性来促进轴突生长的作用，并且可能为解释为什么感觉神经元的外周轴突在损伤后很容易再生，而中枢投射则没有广泛的再生能力提供机制上的见解。
