Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, CA, USA.
Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, CA, USA; Neurosciences Graduate Program, University of California San Diego, La Jolla, CA, USA USA.
Neuron. 2023 Dec 20;111(24):3953-3969.e5. doi: 10.1016/j.neuron.2023.09.019. Epub 2023 Oct 16.
Despite substantial progress in understanding the biology of axon regeneration in the CNS, our ability to promote regeneration of the clinically important corticospinal tract (CST) after spinal cord injury remains limited. To understand regenerative heterogeneity, we conducted patch-based single-cell RNA sequencing on rare regenerating CST neurons at high depth following PTEN and SOCS3 deletion. Supervised classification with Garnett gave rise to a Regeneration Classifier, which can be broadly applied to predict the regenerative potential of diverse neuronal types across developmental stages or after injury. Network analyses highlighted the importance of antioxidant response and mitochondrial biogenesis. Conditional gene deletion validated a role for NFE2L2 (or NRF2), a master regulator of antioxidant response, in CST regeneration. Our data demonstrate a universal transcriptomic signature underlying the regenerative potential of vastly different neuronal populations and illustrate that deep sequencing of only hundreds of phenotypically identified neurons has the power to advance regenerative biology.
尽管在理解中枢神经系统轴突再生的生物学方面取得了重大进展，但我们促进脊髓损伤后临床重要的皮质脊髓束（CST）再生的能力仍然有限。为了了解再生异质性，我们在 PTEN 和 SOCS3 缺失后，对罕见的再生 CST 神经元进行了基于斑块的单细胞 RNA 测序，深度很高。Garnett 的监督分类产生了一个再生分类器，该分类器可以广泛应用于预测不同发育阶段或损伤后各种神经元类型的再生潜力。网络分析强调了抗氧化反应和线粒体生物发生的重要性。条件基因缺失验证了抗氧化反应的主要调节剂 NFE2L2（或 NRF2）在 CST 再生中的作用。我们的数据表明，广泛不同神经元群体的再生潜力具有普遍的转录组特征，并说明仅对数百个表型鉴定的神经元进行深度测序就具有推进再生生物学的能力。
