运动神经元中的Cdon消融导致与年龄相关的运动神经元变性和坐骨神经修复受损。

IF 8.9 1区 医学 Journal of Cachexia, Sarcopenia and Muscle Pub Date : 2023-08-09 DOI:10.1002/jcsm.13308
Sunghee Kim, Subin An, Jinwoo Lee, Yideul Jeong, Chang-Lim You, Hyebeen Kim, Ju-Hyeon Bae, Chae-Eun Yun, Dongryul Ryu, Gyu-Un Bae, Jong-Sun Kang
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引用次数: 0

摘要

背景:运动神经元的功能退化和丧失与退行性运动神经元疾病和衰老相关的肌肉萎缩密切相关。运动神经元疾病或与衰老相关的肌肉萎缩反过来会增加老年人不良健康后果的风险。Cdon(细胞粘附分子下调癌基因)属于细胞粘附分子的免疫球蛋白超家族,在多种信号通路中发挥重要作用,包括声波刺猬(Shh)、netrin和钙粘蛋白介导的信号传导。Cdon作为一种Shh辅助受体,在胚胎发育过程中对运动神经元的指定起着关键作用。然而,它在成人运动神经元功能中的作用尚不清楚。方法:用Hb9-Cre重组酶驱动的运动神经元特异性Cdon缺陷小鼠(mnKO)和复合突变小鼠(mnKO::SOD1G93A)研究Cdon在运动神经元变性中的作用。采用坐骨神经挤压伤模型检测运动神经元的再生。为了研究表型,进行了体力活动、复合肌肉动作电位、免疫染色和透射电子显微镜检查。在机制研究中,采用了RNA测序和RNA/蛋白质分析。结果:运动神经元缺乏Cdon的小鼠表现出中年发病致死性和与衰老相关的运动功能下降。在坐骨神经挤压损伤模型中,mnKO小鼠的运动功能恢复受损,复合肌肉动作电位持续时间延长(f/f为4.63±0.35 vs.3.93±0.22s,P结论:我们目前的数据表明了Cdon在运动神经元功能和神经修复中的功能重要性。Cdon消融导致神经营养素信号改变,导致运动神经元变性。
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Cdon ablation in motor neurons causes age-related motor neuron degeneration and impaired sciatic nerve repair

Background

The functional deterioration and loss of motor neurons are tightly associated with degenerative motor neuron diseases and aging-related muscle wasting. Motor neuron diseases or aging-related muscle wasting in turn contribute to increased risk of adverse health outcomes in the elderly. Cdon (cell adhesion molecule-downregulated oncogene) belongs to the immunoglobulin superfamily of cell adhesion molecule and plays essential roles in multiple signalling pathways, including sonic hedgehog (Shh), netrin, and cadherin-mediated signalling. Cdon as a Shh coreceptor plays a critical role in motor neuron specification during embryonic development. However, its role in adult motor neuron function is unknown.

Methods

Hb9-Cre recombinase-driven motor neuron-specific Cdon deficient mice (mnKO) and a compound mutant mice (mnKO::SOD1G93A) were generated to investigate the role of Cdon in motor neuron degeneration. Motor neuron regeneration was examined by using a sciatic nerve crush injury model. To investigate the phenotype, physical activity, compound muscle action potential, immunostaining, and transmission electron microscopy were carried out. In the mechanism study, RNA sequencing and RNA/protein analyses were employed.

Results

Mice lacking Cdon in motor neurons exhibited middle age onset lethality and aging-related decline in motor function. In the sciatic nerve crush injury model, mnKO mice exhibited an impairment in motor function recovery evident by prolonged compound muscle action potential duration (4.63 ± 0.35 vs. 3.93 ± 0.22 s for f/f, P < 0.01) and physical activity. Consistently, neuromuscular junctions of mnKO muscles were incompletely occupied (49.79 ± 5.74 vs. 79.39 ± 3.77% fully occupied neuromuscular junctions for f/f, P < 0.0001), suggesting an impaired reinnervation. The transmission electron microscopy analysis revealed that mnKO sciatic nerves had smaller axon diameter (0.88 ± 0.13 vs. 1.43 ± 0.48 μm for f/f, P < 0.0001) and myelination defects. RNA sequencing of mnKO lumbar spinal cords showed alteration in genes related to neurogenesis, inflammation and cell death. Among the altered genes, ErbB4 and FgfR expressions were significantly altered in mnKO as well as in Cdon-depleted NSC34 motor neuron cells. Consistently, Cdon-depleted NSC34 cells exhibited elevated levels of cleaved Caspase3 and γH2AX proteins, as well as Bax transcription. Cdon-depleted NSC34 cells also exhibited impaired activation of Akt in response to neuregulin-1 (NRG1) treatment.

Conclusions

Our current data demonstrate the functional importance of Cdon in motor neuron function and nerve repair. Cdon ablation causes alterations in neurotrophin signalling that leads to motor neuron degeneration.

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Journal of Cachexia, Sarcopenia and Muscle
Journal of Cachexia, Sarcopenia and Muscle Medicine-Orthopedics and Sports Medicine
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期刊介绍: The Journal of Cachexia, Sarcopenia, and Muscle is a prestigious, peer-reviewed international publication committed to disseminating research and clinical insights pertaining to cachexia, sarcopenia, body composition, and the physiological and pathophysiological alterations occurring throughout the lifespan and in various illnesses across the spectrum of life sciences. This journal serves as a valuable resource for physicians, biochemists, biologists, dieticians, pharmacologists, and students alike.
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