Nectin-like cell adhesion molecules and the mechanisms of myelination

描述(申请人提供)：轴突-神经胶质相互作用对于髓鞘形成的诱导和有髓纤维的结构域组织是至关重要的。我们最近报道，在外周神经系统(PNS)神经元和髓鞘雪旺细胞中表达一组新的细胞黏附分子，称为NECL蛋白。特别是，轴突上的Necl-1通过与雪旺细胞上的Necl-4特异性结合来介导黏附。我们证明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-神经胶质细胞相互作用的新的、关键的媒介。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的髓鞘形成的。Necl通过其Ig样胞外域调节细胞黏附，并通过FERM和PDZ结合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体。在初步研究中，我们获得了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)，该受体转导了指示性的轴突衍生的髓鞘信号。在体内和体外，我们将结合慢病毒敲除/挽救策略，研究Necl-4的PDZ结合域在雪旺细胞髓鞘形成初期的需求，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受体信号转导。这个项目的总体目标是为调节三叉神经节髓鞘形成的机制提供新的见解。对髓鞘形成所需成分的分子机制的详细了解具有非常重要的意义，并将为开发新的治疗策略以促进外周脱髓鞘神经病的重新髓鞘形成提供有价值的见解。

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.