Nectin-like cell adhesion molecules and the mechanisms of myelination

描述（由申请人提供）：轴突-神经胶质相互作用对于诱导髓鞘形成和有髓鞘纤维的结构域组织至关重要。我们最近报道，在外周神经系统（PNS）神经元和髓鞘雪旺细胞表达一组新的细胞粘附分子称为Nectin样（Necl）蛋白。具体地，轴突上的Necl-1通过特异性结合雪旺细胞上的Necl-4来介导粘附。我们发现Necl-4是启动PNS髓鞘形成所必需的。这些结果暗示Necl蛋白是轴突-神经胶质相互作用的新的重要介质。 一个关键问题是Necl蛋白，特别是Necl-4，如何介导许旺细胞髓鞘形成。Necl通过其Ig样胞外结构域介导细胞粘附，并通过FERM和PDZ结合结构域与支架细胞内蛋白相互作用。通过这些后者的相互作用，Necl蛋白可以组装极性和信号复合物。在初步研究中，我们已经获得了Necl-4与极性蛋白Par-3相互作用的证据。这些研究还指出了Necl-4和雪旺细胞ErbB受体之间可能的相互作用（直接或间接），其抑制了指导性的轴突来源的髓鞘形成信号。 使用Necl-4的突变形式与慢病毒敲减/拯救策略相结合，在体内和体外，我们将表征Necl-4的PDZ结合结构域在雪旺细胞髓鞘形成的初始阶段的需求，解决Necl-4/Par-3相互作用的功能意义，并研究Necl-4如何影响ErbB受体信号传导。 该项目的总体目标是提供新的见解的机制，调节髓鞘形成的PNS。详细了解髓鞘形成所需的分子机制是非常重要的，应该为开发新的治疗策略以促进周围脱髓鞘神经病的髓鞘再生提供有价值的见解。 公共卫生相关性：该项目的总体目标是为PNS中调节轴突-胶质细胞相互作用和髓鞘形成的机制提供新的见解。详细了解髓鞘形成所需的分子机制是非常重要的，应该为开发新的治疗策略以促进周围脱髓鞘神经病的髓鞘再生提供有价值的见解。

DESCRIPTION (provided by applicant): Axon-glial interactions are critical for the induction of myelination and the domain organization of myelinated fibers. We recently reported that in the peripheral nervous system (PNS) neurons and myelinating Schwann cells express a new set of cell adhesion molecules called the Nectin-like (Necl) proteins. In particular, Necl-1 on axons mediates adhesion by specifically binding to Necl-4 on Schwann cells. We showed that Necl-4 is required to initiate PNS myelination. These results implicate the Necl proteins as new, crucial mediators of axon-glia interactions. A key question is how the Necl proteins, and in particular Necl-4, mediates Schwann cell myelination. The Necls mediate cell adhesion though their Ig-like extracellular domain, and interact with scaffolding intracellular proteins through a FERM- and PDZ-binding domains. Through these latter interactions the Necl proteins can assemble polarity and signaling complexes. In preliminary studies we have obtained evidence that Necl-4 interacts with the polarity protein Par-3. These studies have also pointed out a possible interaction (direct or indirect) between Necl-4 and the Schwann cell ErbB receptors that transduce the instructive, axon-derived myelinating signal. Using mutant versions of Necl-4 in combination with lentiviral knockdown/rescue strategies, in vivo an in vitro, we will characterize the requirement of the PDZ-binding domain of Necl-4 in the initial stages of Schwann cell myelination, address the functional significance of the Necl-4/Par-3 interaction, and investigate how Necl-4 influence ErbB receptor signaling. The overall goal of this project is to provide novel insights into the mechanisms that regulate myelin formation in the PNS. A detailed understanding of the molecular mechanism by which components, required for myelination, cooperates is highly significant, and should provide valuable insights for the development of new therapeutic strategies to promote remyelination in peripheral demyelinating neuropathies. PUBLIC HEALTH RELEVANCE: The overall goal of this project is to provide novel insights into the mechanisms that regulate axon- glia interactions and myelin formation in the PNS. A detailed understanding of the molecular mechanism by which components, required for myelination, cooperates is highly significant, and should provide valuable insights for the development of new therapeutic strategies to promote remyelination in peripheral demyelinating neuropathies.