Kawakami Yutaka, Saito Yu, Nakagawa Ryota, Kurihara Yuji, Takei Kohtaro
Molecular Medical Bioscience Laboratory, Department of Medical Life Science, Yokohama City University Graduate School of Medical Life Science, Yokohama 230-0045, Japan.
Molecular Medical Bioscience Laboratory, Department of Medical Life Science, Yokohama City University Graduate School of Medical Life Science, Yokohama 230-0045, Japan.
Neurosci Lett. 2018 Sep 14;683:61-68. doi: 10.1016/j.neulet.2018.06.045. Epub 2018 Jun 25.
There are global efforts in developing therapeutic strategies for central nervous system (CNS) injuries using multimodal approaches. Nogo receptor type 1 (NgR1) has been known as a primary molecule limiting neuronal regeneration in the adult CNS. We identified lateral olfactory tract usher substance (LOTUS) as an endogenous NgR1 antagonist. Membrane-bound LOTUS interacts with NgR1 and inhibits its function by blocking its ligand binding. Five molecules including Nogo, myelin-associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgp), B lymphocyte stimulator (BLyS) and chondroitin sulfate proteoglycans (CSPGs) have been identified as NgR1 ligands. These ligands bind to NgR1 and activate NgR1 signaling, leading to axon growth inhibition such as growth cone collapse and neurite outgrowth inhibition. We have recently reported that the soluble form of LOTUS (s-LOTUS) also suppressed NgR1-mediated signaling induced by myelin axonal inhibitors (MAIs) including Nogo, MAG and OMgp by binding with both NgR1 and its co-receptor p75 neurotrophin receptor (p75). Though s-LOTUS has been reported to suppress MAIs, whether s-LOTUS also suppresses NgR1 signaling induced by BLyS and CSPGs remains to be elucidated. Here, we show that s-LOTUS inhibits NgR1-mediated signaling induced by BLyS and CSPGs. Although treatment with s-LOTUS did not suppress BLyS-NgR1 interaction, s-LOTUS inhibited growth cone collapse and neurite outgrowth inhibition induced by BLyS and CSPGs in chick dorsal root ganglion (DRG) neurons. Furthermore, s-LOTUS compensated for the suppressive function of endogenous LOTUS in NgR1-mediated signaling in olfactory bulb neurons of lotus-knockout mice. These findings suggest that s-LOTUS is a potent therapeutic agent for neuronal regeneration in the CNS injuries.
全球正在努力采用多模式方法开发针对中枢神经系统（CNS）损伤的治疗策略。1型Nogo受体（NgR1）一直被认为是限制成体中枢神经系统中神经元再生的主要分子。我们鉴定出外侧嗅束引导物质（LOTUS）是一种内源性NgR1拮抗剂。膜结合型LOTUS与NgR1相互作用，并通过阻断其配体结合来抑制其功能。包括Nogo、髓鞘相关糖蛋白（MAG）、少突胶质细胞髓鞘糖蛋白（OMgp）、B淋巴细胞刺激因子（BLyS）和硫酸软骨素蛋白聚糖（CSPG）在内的五种分子已被鉴定为NgR1配体。这些配体与NgR1结合并激活NgR1信号传导，导致轴突生长抑制，如生长锥塌陷和神经突生长抑制。我们最近报道，可溶性形式的LOTUS（s-LOTUS）也通过与NgR1及其共受体p75神经营养因子受体（p75）结合，抑制由包括Nogo、MAG和OMgp在内的髓鞘轴突抑制剂（MAI）诱导的NgR1介导的信号传导。尽管已有报道称s-LOTUS可抑制MAI，但s-LOTUS是否也能抑制由BLyS和CSPG诱导的NgR1信号传导仍有待阐明。在此，我们表明s-LOTUS可抑制由BLyS和CSPG诱导的NgR1介导的信号传导。虽然用s-LOTUS处理并未抑制BLyS与NgR1的相互作用，但s-LOTUS可抑制鸡背根神经节（DRG）神经元中由BLyS和CSPG诱导的生长锥塌陷和神经突生长抑制。此外，s-LOTUS弥补了莲花基因敲除小鼠嗅球神经元中内源性LOTUS在NgR1介导的信号传导中的抑制功能。这些发现表明，s-LOTUS是中枢神经系统损伤中神经元再生的一种有效治疗剂。
