Brain Research Institute, University of Zurich, Zurich, Switzerland.
J Cell Biol. 2010 Jan 25;188(2):271-85. doi: 10.1083/jcb.200906089. Epub 2010 Jan 18.
Nogo-A is one of the most potent myelin-associated inhibitors for axonal growth, regeneration, and plasticity in the adult central nervous system. The Nogo-A-specific fragment NogoDelta20 induces growth cone collapse, and inhibits neurite outgrowth and cell spreading by activating RhoA. Here, we show that NogoDelta20 is internalized into neuronal cells by a Pincher- and rac-dependent, but clathrin- and dynamin-independent, mechanism. Pincher-mediated macroendocytosis results in the formation of NogoDelta20-containing signalosomes that direct RhoA activation and growth cone collapse. In compartmentalized chamber cultures, NogoDelta20 is endocytosed into neurites and retrogradely transported to the cell bodies of dorsal root ganglion neurons, triggering RhoA activation en route and decreasing phosphorylated cAMP response element binding levels in cell bodies. Thus, Pincher-dependent macroendocytosis leads to the formation of Nogo-A signaling endosomes, which act both within growth cones and after retrograde transport in the cell body to negatively regulate the neuronal growth program.
Nogo-A 是成年中枢神经系统中对轴突生长、再生和可塑性具有最强抑制作用的髓鞘相关蛋白之一。Nogo-A 特异性片段 NogoDelta20 通过激活 RhoA 诱导生长锥塌陷，并抑制神经突生长和细胞铺展。在这里，我们表明 NogoDelta20 通过 Pincher 和 rac 依赖性、但网格蛋白和动力蛋白独立性机制被内吞到神经元细胞中。Pincher 介导的巨胞饮作用导致形成含有 NogoDelta20 的信号小体，该信号小体可直接激活 RhoA 并导致生长锥塌陷。在分隔的腔室培养物中，NogoDelta20 被内吞到神经突中，并逆行运输到背根神经节神经元的细胞体，在途中触发 RhoA 激活，并降低细胞体中磷酸化 cAMP 反应元件结合物的水平。因此，Pincher 依赖性巨胞饮作用导致 Nogo-A 信号内体的形成，这些内体既在生长锥内发挥作用，又在逆行运输到细胞体后发挥作用，从而负调控神经元生长程序。
