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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DOI：
10.1523/jneurosci.2076-22.2023
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发表时间：
2023-06-28
影响因子：
5.3
通讯作者：
Fawcett, James W.
中科院分区：
文献类型：
--
作者：
Cheah, Menghon;Cheng, Yuyan;Petrova, Veselina;Cimpean, Anda;Jendelova, Pavla;Swarup, Vivek;Woolf, Clifford J.;Geschwind, Daniel H.;Fawcett, James W.
与脊髓的中央分支不同，感觉背根神经节（DRG）神经元的外周分支在受伤后很容易再生。然而，脊髓中感觉轴突的广泛再生和重新连接可以由 α9 整合素及其激活剂 kindlin-1 (α9k1) 的表达驱动，使轴突能够与腱蛋白-C 相互作用。为了阐明受激活的整合素表达和中枢再生影响的机制和下游途径，我们对用 α9k1 转导的成年雄性大鼠 DRG 感觉神经元和对照（有或没有中央分支轴索切除术）进行了转录组分析。没有中央轴切开术的 α9k1 表达导致已知的 PNS 再生程序上调，包括许多与周围神经再生相关的基因。将 α9k1 治疗与背根轴突切除术相结合可导致广泛的中央轴突再生。除了α9k1表达上调的程序外，脊髓的再生还导致独特的中枢神经系统再生程序的表达，包括与泛素化、自噬、内质网（ER）、运输和信号传导相关的基因。对这些过程的药理学抑制可阻止 DRG 和人类 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。这种与中枢神经系统再生相关的程序与胚胎发育或三七总皂甙再生程序几乎没有相关性。该 CNS 程序与再生耦合的潜在转录驱动因素包括 Mef2a、Runx3、E2f4 和 Yy1。整合素发出的信号为感觉神经元的再生做好准备，但它们在中枢神经系统中的轴突生长与一个与三七总皂甙再生不同的额外独特程序相关。意义声明 人类患者脊髓损伤后神经功能的恢复尚未实现。为了实现这一目标，必须使切断的神经纤维再生。神经通路的重建一直是不可能的，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被开发出来。这项研究利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种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。该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 STATEMENT Restoration 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.
影响因子：
5.7
作者：
Onishi K;Hollis E;Zou Y
通讯作者：
Zou Y