Integrin-driven Axon Regeneration in the Spinal Cord Activates a Distinctive CNS Regeneration Program
Integrin-driven Axon Regeneration in the Spinal Cord Activates a Distinctive CNS Regeneration Program
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整合素驱动的脊髓轴突再生激活了独特的中枢神经系统再生程序
DOI：
10.1101/2021.12.07.471602
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Cheah M
中科院分区：
文献类型：
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作者：
Cheah M
感觉背根神经节（DRG）神经元的外周分支在损伤后很容易再生，不像它们在脊髓中的中央分支。然而，脊髓中感觉轴突的广泛再生和重新连接可以通过α9整合素及其激活剂kindlin-1（α 9 k1）的表达来驱动，这使得轴突能够与腱生蛋白-C相互作用。为了阐明活化整合素表达和中枢再生影响的机制和下游通路，我们对用α 9 k1转导的成年雄性大鼠DRG感觉神经元和对照进行了转录组学分析，其中有和没有中央分支的轴突切断。α 9 k1在没有中枢神经切断的情况下的表达导致了已知的PNS再生程序的上调，包括许多与周围神经再生相关的基因。α 9 k1联合背根切断可引起广泛的中枢轴突再生。除了α 9 k1表达上调的程序外，脊髓再生导致独特的CNS再生程序的表达，包括与泛素化、自噬、内质网（ER）、运输和信号传导相关的基因。这些过程的药理学抑制阻断了DRG和人iPSC衍生的感觉神经元的轴突再生，验证了它们对感觉再生的因果贡献。这种中枢神经系统再生相关的程序与胚胎发育或PNS再生程序几乎没有相关性。与再生偶联的该CNS程序的潜在转录驱动因子包括Mef 2a、Runx 3、E2 f4和YY 1。来自整合素的信号传导引发感觉神经元的再生，但它们在CNS中的轴突生长与另外一个不同于参与PNS再生的独特程序相关。要做到这一点，切断的神经纤维必须再生。神经通路的重建是不可能的，但最近，一种刺激啮齿动物感觉纤维长距离轴突再生的方法已经开发出来。这项研究使用再生感觉神经元中信使RNA的分析来发现哪些机制被激活。这项研究表明，再生神经元启动了一个新的中枢神经系统再生程序，其中包括分子运输，自噬，泛素化，和内质网（ER）的调节。这项研究确定了神经元需要激活以再生神经纤维的机制。
The peripheral branch of sensory dorsal root ganglion (DRG) neurons regenerates readily after injury unlike their central branch in the spinal cord. However, extensive regeneration and reconnection of sensory axons in the spinal cord can be driven by the expression of α9 integrin and its activator kindlin-1 (α9k1), which enable axons to interact with tenascin-C. To elucidate the mechanisms and downstream pathways affected by activated integrin expression and central regeneration, we conducted transcriptomic analyses of adult male rat DRG sensory neurons transduced with α9k1, and controls, with and without axotomy of the central branch. Expression of α9k1 without the central axotomy led to upregulation of a known PNS regeneration program, including many genes associated with peripheral nerve regeneration. Coupling α9k1 treatment with dorsal root axotomy led to extensive central axonal regeneration. In addition to the program upregulated by α9k1 expression, regeneration in the spinal cord led to expression of a distinctive CNS regeneration program, including genes associated with ubiquitination, autophagy, endoplasmic reticulum (ER), trafficking, and signaling. Pharmacological inhibition of these processes blocked the regeneration of axons from DRGs and human iPSC-derived sensory neurons, validating their causal contributions to sensory regeneration. This CNS regeneration-associated program showed little correlation with either embryonic development or PNS regeneration programs. Potential transcriptional drivers of this CNS program coupled to regeneration include Mef2a, Runx3, E2f4, and Yy1. Signaling from integrins primes sensory neurons for regeneration, but their axon growth in the CNS is associated with an additional distinctive program that differs from that involved in PNS regeneration.SIGNIFICANCE STATEMENTRestoration of neurologic function after spinal cord injury has yet to be achieved in human patients. To accomplish this, severed nerve fibers must be made to regenerate. Reconstruction of nerve pathways has not been possible, but recently, a method for stimulating long-distance axon regeneration of sensory fibers in rodents has been developed. This research uses profiling of messenger RNAs in the regenerating sensory neurons to discover which mechanisms are activated. This study shows that the regenerating neurons initiate a novel CNS regeneration program which includes molecular transport, autophagy, ubiquitination, and modulation of the endoplasmic reticulum (ER). The study identifies mechanisms that neurons need to activate to regenerate their nerve fibers.