Benson M Douglas, Romero Mario I, Lush Mark E, Lu Q Richard, Henkemeyer Mark, Parada Luis F
Center for Developmental Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-9133, USA.
Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10694-9. doi: 10.1073/pnas.0504021102. Epub 2005 Jul 14.
The inability of CNS axons to regenerate after traumatic spinal cord injury is due, in part, to the inhibitory effects of myelin. The three major previously identified constituents of this activity (Nogo, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein) were isolated based on their potent inhibition of axon outgrowth in vitro. All three myelin components transduce their inhibitory signals through the same Nogo receptor/p75 neurotrophin receptor/LINGO-1 (NgR1/p75/LINGO-1) complex. In this study, we considered that molecules known to act as repellants in vertebrate embryonic axonal pathfinding may also inhibit regeneration. In mice, ephrin-B3 functions during development as a midline repellant for axons of the corticospinal tract. We therefore investigated whether this repellant was expressed in the adult spinal cord and retained inhibitory activity. We demonstrate that ephrin-B3 is expressed in postnatal myelinating oligodendrocytes and, by using primary CNS neurons, show that ephrin-B3 accounts for an inhibitory activity equivalent to that of the other three myelin-based inhibitors, acting through p75, combined. Our data describe a known vertebrate axon guidance molecule as a myelin-based inhibitor of neurite outgrowth.
创伤性脊髓损伤后中枢神经系统轴突无法再生，部分原因是髓磷脂的抑制作用。先前确定的这种活性的三种主要成分（Nogo、髓磷脂相关糖蛋白和少突胶质细胞髓磷脂糖蛋白）是基于它们在体外对轴突生长的强大抑制作用而分离出来的。所有三种髓磷脂成分都通过相同的Nogo受体/p75神经营养因子受体/LINGO-1（NgR1/p75/LINGO-1）复合物转导其抑制信号。在本研究中，我们认为在脊椎动物胚胎轴突导向中已知起排斥作用的分子也可能抑制再生。在小鼠中，ephrin-B3在发育过程中作为皮质脊髓束轴突的中线排斥物发挥作用。因此，我们研究了这种排斥物在成年脊髓中是否表达并保留抑制活性。我们证明ephrin-B3在出生后形成髓鞘的少突胶质细胞中表达，并通过使用原代中枢神经系统神经元表明，ephrin-B3的抑制活性相当于其他三种基于髓磷脂的抑制剂通过p75共同作用的抑制活性。我们的数据将一种已知的脊椎动物轴突导向分子描述为基于髓磷脂的神经突生长抑制剂。
