Udina Esther, Putman Charles T, Harris Luke R, Tyreman Neil, Cook Victoria E, Gordon Tessa
Neuroscience and Mental Health Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada, T6G 2S2.
Institute of Neurosciences and Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain.
J Physiol. 2017 Mar 1;595(5):1815-1829. doi: 10.1113/JP273404. Epub 2017 Jan 25.
Smn transgenic mouse is a model of the mildest form of spinal muscular atrophy. Although there is a loss of spinal motoneurons in 11-month-old animals, muscular force is maintained. This maintained muscular force is mediated by reinnervation of the denervated fibres by surviving motoneurons. The spinal motoneurons in these animals do not show an increased susceptibility to death after nerve injury and they retain their regenerative capacity. We conclude that the hypothesized immaturity of the neuromuscular system in this model cannot explain the loss of motoneurons by systematic die-back.
Spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans and is the leading genetic cause of infantile death. Patients lack the SMN1 gene with the severity of the disease depending on the number of copies of the highly homologous SMN2 gene. Although motoneuron death in the Smn transgenic mouse model of the mildest form of SMA, SMA type III, has been reported, we have used retrograde tracing of sciatic and femoral motoneurons in the hindlimb with recording of muscle and motor unit isometric forces to count the number of motoneurons with intact neuromuscular connections. Thereby, we investigated whether incomplete maturation of the neuromuscular system induced by survival motoneuron protein (SMN) defects is responsible for die-back of axons relative to survival of motoneurons. First, a reduction of ∼30% of backlabelled motoneurons began relatively late, at 11 months of age, with a significant loss of 19% at 7 months. Motor axon die-back was affirmed by motor unit number estimation. Loss of functional motor units was fully compensated by axonal sprouting to retain normal contractile force in four hindlimb muscles (three fast-twitch and one slow-twitch) innervated by branches of the sciatic nerve. Second, our evaluation of whether axotomy of motoneurons in the adult Smn transgenic mouse increases their susceptibility to cell death demonstrated that all the motoneurons survived and they sustained their capacity to regenerate their nerve fibres. It is concluded the systematic die-back of motoneurons that innervate both fast- and slow-twitch muscle fibres is not related to immaturity of the neuromuscular system in SMA.
SMN转基因小鼠是最轻微形式的脊髓性肌萎缩症模型。尽管11个月大的动物存在脊髓运动神经元缺失，但肌肉力量得以维持。这种维持的肌肉力量是由存活的运动神经元对失神经纤维的重新支配介导的。这些动物的脊髓运动神经元在神经损伤后对死亡的易感性并未增加，并且保留了它们的再生能力。我们得出结论，该模型中假设的神经肌肉系统不成熟不能解释运动神经元通过系统性退行性变而丧失的现象。
脊髓性肌萎缩症（SMA）是人类常见的常染色体隐性疾病，是婴儿死亡的主要遗传原因。患者缺乏SMN1基因，疾病的严重程度取决于高度同源的SMN2基因的拷贝数。尽管已经报道了最轻微形式的SMA（III型SMA）的Smn转基因小鼠模型中运动神经元死亡的情况，但我们使用坐骨神经和股运动神经元的逆行追踪技术，同时记录肌肉和运动单位的等长力，以计算具有完整神经肌肉连接的运动神经元数量。由此，我们研究了由存活运动神经元蛋白（SMN）缺陷引起的神经肌肉系统不完全成熟是否是轴突相对于运动神经元存活的退行性变的原因。首先，约30%的逆向标记运动神经元减少相对较晚开始，在11个月大时出现，7个月时显著减少19%。运动单位数量估计证实了运动轴突的退行性变。坐骨神经分支支配的四条后肢肌肉（三条快肌和一条慢肌）中，功能性运动单位的丧失通过轴突发芽得到了完全补偿，以维持正常的收缩力。其次，我们对成年Smn转基因小鼠运动神经元轴突切断是否会增加其对细胞死亡的易感性的评估表明，所有运动神经元都存活下来，并且它们维持了再生神经纤维的能力。得出的结论是，支配快肌和慢肌纤维的运动神经元的系统性退行性变与SMA中神经肌肉系统的不成熟无关。
