Counteracting the Nogo receptor enhances optic nerve regeneration if retinal ganglion cells are in an active growth state
Counteracting the Nogo receptor enhances optic nerve regeneration if retinal ganglion cells are in an active growth state
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DOI：
10.1523/jneurosci.5119-03.2004
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发表时间：
2004-02-18
影响因子：
5.3
通讯作者：
Benowitz, LI
中科院分区：
文献类型：
--
作者：
Fischer, D;He, ZG;Benowitz, LI
成熟的视网膜神经节细胞（RGCs），像其他中枢神经系统神经元一样，不能在富含髓鞘的环境中再生受损的轴突。然而，如果受到巨噬细胞衍生因子的刺激，RGCs可以通过远端视神经再生相当长的轴突。利用这种“敏感背景”，我们研究了增加Nogo受体（NgR）表达或抑制其活性的影响。NgR介导三种髓鞘蛋白Nogo、OMgp（少突胶质-髓鞘糖蛋白）和MAG（髓鞘相关糖蛋白）的生长抑制作用。用表达NgR显性阴性形式（NgRDN）的腺相关病毒转染生长致敏的RGCs，可使轴突再生增加数倍；然而，当RGCs的生长程序未被激活时，NgRDN的表达没有任何有益的影响。野生型NgR的过表达几乎阻断了生长致敏RGCs的所有再生，并导致病变部位近端轴突缩回。我们得出结论，基因治疗是促进中枢神经系统轴突再生的有效途径，在激活神经元固有生长程序的情况下，NgR功能失活可大大促进轴突再生。
Mature retinal ganglion cells (RGCs), like other CNS neurons, cannot regrow injured axons into a myelin-rich environment. If stimulated by macrophage-derived factors, however, RGCs can regenerate their axons for considerable distances through the distal optic nerve. Using this "sensitized background," we investigated the effects of either increasing the expression or suppressing the activity of the Nogo receptor (NgR). NgR mediates the growth-inhibiting effects of three myelin proteins, Nogo, OMgp (oligodendrocyte-myelin glycoprotein), and MAG (myelin-associated glycoprotein). Transfecting growth-sensitized RGCs with adeno-associated viruses expressing a dominant-negative form of NgR (NgRDN) increased axon regeneration several-fold; however, when the growth program of RGCs was not activated, NgRDN expression had no beneficial effects. Overexpression of wild-type NgR blocked almost all regeneration from growth-sensitized RGCs and caused axons proximal to the lesion site to retract. We conclude that gene therapy is an effective approach to enhancing axon regeneration in the CNS and that inactivation of NgR functioning greatly enhances axon regeneration provided the intrinsic growth program of neurons is activated.