Nectin-like cell adhesion molecules and the mechanisms of myelination

描述（由申请人提供）：轴突-胶质相互作用是诱导髓鞘形成和髓鞘纤维结构域组织的关键。我们最近报道了外周神经系统（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。特别是，轴突上的Necl-1通过特异性结合雪旺细胞上的Necl-4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-胶质细胞相互作用的新的关键介质。一个关键的问题是Necl蛋白，特别是Necl-4是如何介导雪旺细胞髓鞘形成的。Necls通过其类似igg的胞外结构域介导细胞粘附，并通过FERM-和pdz结合结构域与细胞内支架蛋白相互作用。通过后一种相互作用，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，Necl-4与雪旺细胞ErbB受体之间可能存在直接或间接的相互作用，这些相互作用可转导指导性的轴突源性髓鞘形成信号。在体内和体外实验中，我们将利用突变型的Necl-4结合慢病毒敲除/拯救策略，表征雪旺细胞髓鞘形成初始阶段对Necl-4 pdz结合域的需求，探讨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为PNS中髓磷脂形成的调节机制提供新的见解。详细了解髓鞘形成所需成分的分子机制是非常重要的，并且应该为开发新的治疗策略来促进周围脱髓鞘神经病变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.