Department of Physiology and Green Center for Systems Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States of America.
PLoS Biol. 2010 Dec 7;8(12):e1000553. doi: 10.1371/journal.pbio.1000553.
Axon pathfinding and synapse formation rely on precise spatiotemporal localization of guidance receptors. However, little is known about the neuron-specific intracellular trafficking mechanisms that underlie the sorting and activity of these receptors. Here we show that loss of the neuron-specific v-ATPase subunit a1 leads to progressive endosomal guidance receptor accumulations after neuronal differentiation. In the embryo and in adult photoreceptors, these accumulations occur after axon pathfinding and synapse formation is complete. In contrast, receptor missorting occurs sufficiently early in neurons of the adult central nervous system to cause connectivity defects. An increase of guidance receptors, but not of membrane proteins without signaling function, causes specific gain-of-function phenotypes. A point mutant that promotes sorting but prevents degradation reveals spatiotemporally specific guidance receptor turnover and accelerates developmental defects in photoreceptors and embryonic motor neurons. Our findings indicate that a neuron-specific endolysosomal degradation mechanism is part of the cell biological machinery that regulates guidance receptor turnover and signaling.
轴突导向和突触形成依赖于指导受体的精确时空定位。然而，对于这些受体的分类和活性所依赖的神经元特异性细胞内运输机制知之甚少。在这里，我们发现神经元特异性 v-ATPase 亚基 a1 的缺失会导致神经元分化后内体指导受体的逐渐积累。在胚胎和成年光感受器中，这些积累发生在轴突导向和突触形成完成之后。相比之下，在成年中枢神经系统的神经元中，受体分选错误发生得足够早，导致连接缺陷。指导受体的增加，但没有信号功能的膜蛋白的增加，会导致特定的功能获得表型。一种促进分选但阻止降解的点突变揭示了时空特异性的指导受体周转，并加速了光感受器和胚胎运动神经元的发育缺陷。我们的发现表明，神经元特异性内溶酶体降解机制是调节指导受体周转和信号的细胞生物学机制的一部分。
