Mi Sha, Miller Robert H, Lee Xinhua, Scott Martin L, Shulag-Morskaya Svetlane, Shao Zhaohui, Chang Jufang, Thill Greg, Levesque Melissa, Zhang Mingdi, Hession Cathy, Sah Dinah, Trapp Bruce, He Zhigang, Jung Vincent, McCoy John M, Pepinsky R Blake
Department of Discovery Biology, Biogen Idec, Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142, USA.
Nat Neurosci. 2005 Jun;8(6):745-51. doi: 10.1038/nn1460. Epub 2005 May 15.
The control of myelination by oligodendrocytes in the CNS is poorly understood. Here we show that LINGO-1 is an important negative regulator of this critical process. LINGO-1 is expressed in oligodendrocytes. Attenuation of its function by dominant-negative LINGO-1, LINGO-1 RNA-mediated interference (RNAi) or soluble human LINGO-1 (LINGO-1-Fc) leads to differentiation and increased myelination competence. Attenuation of LINGO-1 results in downregulation of RhoA activity, which has been implicated in oligodendrocyte differentiation. Conversely, overexpression of LINGO-1 leads to activation of RhoA and inhibition of oligodendrocyte differentiation and myelination. Treatment of oligodendrocyte and neuron cocultures with LINGO-1-Fc resulted in highly developed myelinated axons that have internodes and well-defined nodes of Ranvier. The contribution of LINGO-1 to myelination was verified in vivo through the analysis of LINGO-1 knockout mice. The ability to recapitulate CNS myelination in vitro using LINGO-1 antagonists and the in vivo effects seen in the LINGO-1 knockout indicate that LINGO-1 signaling may be critical for CNS myelination.
中枢神经系统中少突胶质细胞对髓鞘形成的控制目前还了解甚少。在此我们表明，LINGO-1是这一关键过程的重要负调控因子。LINGO-1在少突胶质细胞中表达。通过显性负性LINGO-1、LINGO-1 RNA介导的干扰（RNAi）或可溶性人LINGO-1（LINGO-1-Fc）减弱其功能，会导致分化并提高髓鞘形成能力。LINGO-1的减弱导致RhoA活性下调，而RhoA活性与少突胶质细胞分化有关。相反，LINGO-1的过表达会导致RhoA激活，并抑制少突胶质细胞分化和髓鞘形成。用LINGO-1-Fc处理少突胶质细胞和神经元共培养物，会产生高度发达的有髓轴突，这些轴突有节间和明确的郎飞结。通过对LINGO-1基因敲除小鼠的分析，在体内验证了LINGO-1对髓鞘形成的作用。使用LINGO-1拮抗剂在体外重现中枢神经系统髓鞘形成的能力以及在LINGO-1基因敲除小鼠中观察到的体内效应表明，LINGO-1信号传导可能对中枢神经系统髓鞘形成至关重要。
