The downregulation of growth-associated proteins in motoneurons at the onset of synapse elimination is controlled by muscle activity and IGF1-猫眼课题宝

突触消除开始时运动神经元中生长相关蛋白的下调由肌肉活动和 IGF1 控制

DOI：

10.1523/jneurosci.12-10-03849.1992

发表时间：

1992

期刊：

Expert Reviews in Molecular Medicine

影响因子：

6.2

通讯作者：

中科院分区：

医学2区

文献类型：

作者：

P. Caroni;M. Becker

在发育和再生过程中，轴突的生长与生长相关蛋白(GAP)的表达相一致，包括GAP-43和微管蛋白-α1。在与靶区和突触发生接触后，GAP被下调。然而，在成年CNS的一些神经元中有高水平的GAP-43表达，这表明其功能可能并不局限于轴突生长。为了确定在发育过程中调节GAP水平的信号类型，我们确定了GAP下调是否与突触发育的特定阶段一致，以及它是否受突触后靶点的控制。在鸡和大鼠发育的神经肌肉系统中，分析了脊髓运动神经元GAP-43mRNA和神经肌肉交界处蛋白的表达水平。在这两个物种中，GAP-43mRNA在突触消除开始时迅速下降，神经末梢GAP-43免疫反应消失，延迟2-3d。在大鼠运动神经元中，GAP-43和微管蛋白-α1mRNA水平以相似的时间进程下降，表明至少有两个GAP同时下调。用突触前或突触后作用的毒素阻断神经肌肉传递可以阻止GAP下调，这表明靶活动影响运动神经元中的GAP mRNA水平。最后，局部皮下注射抵消了突触消除过程中肌肉胰岛素样生长因子的活性依赖性下降，阻止了运动神经元间隙的下调，表明这些生长因子可能参与了肌肉对运动神经元间隙的调节。这些结果表明，在突触消除开始时，运动神经元在间隙中经历靶敏感的变化。此外，这些结果提出了终止突触前生长模式可能是突触消除的先决条件。

Axonal growth during development and regeneration coincides with the expression of growth-associated proteins (GAPs), including GAP-43 and tubulin-alpha 1. Following contact with the target region and synaptogenesis, GAPs are downregulated. However, high levels of GAP-43 are expressed in some neurons in the adult CNS, indicating that its function may not be restricted to axonal growth. To define the type of signals that regulate GAP levels during development, we have determined whether GAP downregulation coincides with a defined phase of synapse development and whether it is controlled by the postsynaptic target. Levels of GAP-43 mRNA in spinal motoneurons and protein at the neuromuscular junction were analyzed in the developing neuromuscular system of chick and rat. In both species, GAP-43 mRNA declined rapidly at a time corresponding to the onset of synapse elimination, and nerve terminal GAP-43 immunoreactivity became undetectable with a delay of 2- 3 d. In rat motoneurons, GAP-43 and tubulin-alpha 1 mRNA levels declined with a similar time course, indicating that at least two GAPs are downregulated at the same time. Blockade of neuromuscular transmission with either a pre- or a postsynaptically acting toxin prevented GAP downregulation, indicating that target activity affects GAP mRNA levels in motoneurons. Finally, counteracting the activity- dependent decline of muscle insulin-like growth factors during synapse elimination by local subcutaneous injections prevented motoneuron GAP downregulation, suggesting that these growth factors may be involved in the regulation of motoneuron GAPs by the muscle. These results demonstrate that motoneurons undergo target-sensitive changes in GAPs at the onset of synapse elimination. In addition, these results raise the possibility that termination of a presynaptic growth mode may be a prerequisite for synapse elimination.