Neuromuscular development in the absence of programmed cell death: Phenotypic alteration of motoneurons and muscle
Neuromuscular development in the absence of programmed cell death: Phenotypic alteration of motoneurons and muscle
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DOI：
10.1523/jneurosci.3528-06.2006
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发表时间：
2006-12-27
影响因子：
5.3
通讯作者：
Oppenheim, Ronald W.
中科院分区：
文献类型：
--
作者：
Buss, Robert R.;Gould, Thomas W.;Oppenheim, Ronald W.
鸟类和哺乳动物的中枢和周围神经系统中发育中的神经元普遍大量丧失，通常被认为是一种进化适应。然而，直到最近，还没有用于测试防止这种正常细胞损失的直接和长期后果的模型。我们利用了几种预防体内神经元死亡的方法来询问是否可以挽救神经元[例如。例如，运动神经元（MN）]正常分化并在功能上融入神经系统。尽管在预防细胞死亡后，MN 分化的许多方面正常发生（包括几种运动神经元特异性标记物的表达、轴突投射到腹侧根和周围神经、超微结构、树突分枝和传入轴体突触），但神经肌肉系统（MN 和肌肉）的其他特征是异常的。 MN 的细胞体和轴突比正常小，许多 MN 轴突未能形成有髓鞘或与目标肌肉形成功能性突触接触，并且被拯救的细胞亚群从 α 型 MN 转变为 γ 型 MN。此外，在肌细胞生成素胶质细胞系源性神经营养因子（MyoGDNF）转基因小鼠中挽救MN后，梭外骨骼肌的肌纤维分化发生改变，肌肉生理和运动行为异常。相比之下，通过促凋亡基因 Bax 的基因删除来拯救 MN 后，梭外肌纤维表型、肌肉生理学和（肌肉力量测试除外）运动行为均正常。然而，与野生型和 MyoGDNF 小鼠相比，Bax 敲除小鼠的梭内肌纤维（纺锤体）有所增加。总之，这些数据表明，在预防 MN 死亡后，神经肌肉系统会以新的方式发生转变，以补偿数千个多余细胞的存在。
The widespread, massive loss of developing neurons in the central and peripheral nervous system of birds and mammals is generally considered to be an evolutionary adaptation. However, until recently, models for testing both the immediate and long-term consequences of preventing this normal cell loss have not been available. We have taken advantage of several methods for preventing neuronal death in vivo to ask whether rescued neurons [ e. g., motoneurons (MNs)] differentiate normally and become functionally incorporated into the nervous system. Although many aspects of MN differentiation occurred normally after the prevention of cell death ( including the expression of several motoneuron-specific markers, axon projections into the ventral root and peripheral nerves, ultrastructure, dendritic arborization, and afferent axosomatic synapses), other features of the neuromuscular system (MNs and muscle) were abnormal. The cell bodies and axons of MNs were smaller than normal, many MN axons failed to become myelinated or to form functional synaptic contacts with target muscles, and a subpopulation of rescued cells were transformed from alpha- to gamma-like MNs. Additionally, after the rescue of MNs in myogenin glial cell line-derived neurotrophic factor (MyoGDNF) transgenic mice, myofiber differentiation of extrafusal skeletal muscle was transformed and muscle physiology and motor behaviors were abnormal. In contrast, extrafusal myofiber phenotype, muscle physiology, and ( except for muscle strength tests) motor behaviors were all normal after the rescue of MNs by genetic deletion of the proapoptotic gene Bax. However, there was an increase in intrafusal muscle fibers ( spindles) in Bax knock-out versus both wild-type and MyoGDNF mice. Together, these data indicate that after the prevention of MN death, the neuromuscular system becomes transformed in novel ways to compensate for the presence of the thousands of excess cells.