Motoneuron development influences dorsal root ganglia survival and Schwann cell development in a vertebrate model of spinal muscular atrophy
Motoneuron development influences dorsal root ganglia survival and Schwann cell development in a vertebrate model of spinal muscular atrophy
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DOI：
10.1093/hmg/ddu447
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发表时间：
2015-01-15
影响因子：
3.5
通讯作者：
Beattie, Christine E.
中科院分区：
文献类型：
--
作者：
Le Thi Hao;Duy, Phan Q.;Beattie, Christine E.
运动神经元存活蛋白（SMN）水平低导致脊髓性肌萎缩症。这种疾病的主要特征是运动神经元功能障碍和瘫痪。了解为什么运动神经元受到低水平SMN的影响将有助于深入了解这种疾病和运动神经元生物学。斑马鱼SMN突变体中的运动神经元发育异常;然而，由于SMN是一种普遍表达的蛋白质，因此尚不清楚SMN在运动神经元发育中的作用。我们已经解决了这个问题，表达人类SMN在运动神经元中的斑马鱼母合子（MZ）SMN突变体。首先，我们证明了SMN存在于轴突中，但仅在强大的运动轴突生长期间。我们也最终证明，SMN行为细胞自主运动神经元适当的运动神经元的发展。这包括轴突和树突分支的形成。周围神经系统的分析表明，雪旺细胞和背根神经节（DRG）神经元异常发育的mz-smn突变体。雪旺细胞没有紧密包裹轴突，并有扩大的朗维尔结。大多数DRG神经元具有异常短的外周轴突，随后许多神经元不能分裂并死亡。仅在运动神经元中表达SMN拯救了这两种细胞类型，表明它们的发育失败是继发于运动神经元的发育缺陷。仅在运动神经元中驱动SMN并没有增加动物的存活率，这表明运动神经元发育和运动回路需要SMN，但其他细胞类型中的SMN影响存活。
Low levels of the survival motor neuron protein (SMN) cause the disease spinal muscular atrophy. A primary characteristic of this disease is motoneuron dysfunction and paralysis. Understanding why motoneurons are affected by low levels of SMN will lend insight into this disease and to motoneuron biology in general. Motoneurons in zebrafish smn mutants develop abnormally; however, it is unclear where Smn is needed for motoneuron development since it is a ubiquitously expressed protein. We have addressed this issue by expressing human SMN in motoneurons in zebrafish maternal-zygotic (mz) smn mutants. First, we demonstrate that SMN is present in axons, but only during the period of robust motor axon outgrowth. We also conclusively demonstrate that SMN acts cell autonomously in motoneurons for proper motoneuron development. This includes the formation of both axonal and dendritic branches. Analysis of the peripheral nervous system revealed that Schwann cells and dorsal root ganglia (DRG) neurons developed abnormally in mz-smn mutants. Schwann cells did not wrap axons tightly and had expanded nodes of Ranvier. The majority of DRG neurons had abnormally short peripheral axons and later many of them failed to divide and died. Expressing SMN just in motoneurons rescued both of these cell types showing that their failure to develop was secondary to the developmental defects in motoneurons. Driving SMN just in motoneurons did not increase survival of the animal, suggesting that SMN is needed for motoneuron development and motor circuitry, but that SMN in other cells types factors into survival.