Axonal regeneration and functional recovery driven by endogeneous Nogo receptor antagonist LOTUS in a rat model of unilateral pyramidotomy.
Axonal regeneration and functional recovery driven by endogeneous Nogo receptor antagonist LOTUS in a rat model of unilateral pyramidotomy.
复制标题
在单侧锥体切开术大鼠模型中内源性 Nogo 受体拮抗剂 LOTUS 驱动的轴突再生和功能恢复。
DOI：
10.1016/j.expneurol.2019.113068
复制
发表时间：
2020
影响因子：
5.3
通讯作者：
and Yamamoto
中科院分区：
文献类型：
--
作者：
Ueno;R.;Takase;H.;Suenaga;J.;Kishimoto;M.;Kurihara;Y.;Takei;K.;Kawahara;N.;and Yamamoto
成年哺乳动物的中枢神经系统(CNS)很少能从损伤中恢复。髓鞘片段含有限制轴突再生的轴突生长抑制物，因此在决定神经恢复方面发挥着重要作用。Nogo受体-1(NgR1)及其配体是限制轴突再生的抑制剂之一。已有研究表明，在小鼠脊髓损伤和脑缺血后，内源性蛋白--外侧嗅束引导物(Lotus)可拮抗NgR1介导的信号转导，促进神经元的可塑性。然而，目前尚不清楚莲花介导的成人大脑下行运动通路的重组是否具有生理功能，是否有助于功能恢复。在此，我们建立了莲花过表达转基因大鼠(Lotus-TG)，以研究莲花对损伤后神经功能的影响。切断一侧锥体后，与野生型动物相比，莲花-TG大鼠的运动功能明显恢复。在逆行示踪研究中，莲花-甘油三酯大鼠颈髓损伤侧至红核健侧和感觉运动皮质的标记轴突增多。来自未损毁皮质的顺行追踪也显示，莲花-甘油三酯大鼠同侧至受损颈髓的连通性增强。此外，电生理分析显示，对侧皮质刺激显著增加了Lotus-TG大鼠的同侧前肢运动，这与组织学结果一致。根据这些数据，单侧锥体切开术后，莲花的过度表达加速了同侧大脑皮质的投射，促进了功能的恢复。莲花可能是未来治疗中枢神经系统损伤的一种选择。
The adult mammalian central nervous system (CNS) rarely recovers from injury. Myelin fragments contain axonal growth inhibitors that limit axonal regeneration, thus playing a major role in determining neural recovery. Nogo receptor-1 (NgR1) and its ligands are among the inhibitors that limit axonal regeneration. It has been previously shown that the endogenous protein, lateral olfactory tract usher substance (LOTUS), antagonizes NgR1-mediated signaling and accelerates neuronal plasticity after spinal cord injury and cerebral ischemia in mice. However, it remained unclear whether LOTUS-mediated reorganization of descending motor pathways in the adult brain is physiologically functional and contributes to functional recovery. Here, we generated LOTUS-overexpressing transgenic (LOTUS-Tg) rats to investigate the role of LOTUS in neuronal function after damage. After unilateral pyramidotomy, motor function in LOTUS-Tg rats recovered significantly compared to that in wild-type animals. In a retrograde tracing study, labeled axons spanning from the impaired side of the cervical spinal cord to the unlesioned hemisphere of the red nucleus and sensorimotor cortex were increased in LOTUS-Tg rats. Anterograde tracing from the unlesioned cortex also revealed enhanced ipsilateral connectivity to the impaired side of the cervical spinal cord in LOTUS-Tg rats. Moreover, electrophysiological analysis showed that contralesional cortex stimulation significantly increased ipsilateral forelimb movement in LOTUS-Tg rats, which was consistent with the histological findings. According to these data, LOTUS overexpression accelerates ipsilateral projection from the unlesioned cortex and promotes functional recovery after unilateral pyramidotomy. LOTUS could be a future therapeutic option for CNS injury.