Department of Molecular Biology, Chonbuk National University, Jeonju, Jeollabukdo 54896, Republic of Korea;
Department of Molecular Biology, Chonbuk National University, Jeonju, Jeollabukdo 54896, Republic of Korea.
Proc Natl Acad Sci U S A. 2017 Sep 26;114(39):E8254-E8263. doi: 10.1073/pnas.1713010114. Epub 2017 Sep 11.
The transmembrane semaphorin Sema-1a acts as both a ligand and a receptor to regulate axon-axon repulsion during neural development. Pebble (Pbl), a Rho guanine nucleotide exchange factor, mediates Sema-1a reverse signaling through association with the N-terminal region of the Sema-1a intracellular domain (ICD), resulting in cytoskeletal reorganization. Here, we uncover two additional Sema-1a interacting proteins, varicose (Vari) and cheerio (Cher), each with neuronal functions required for motor axon pathfinding. Vari is a member of the membrane-associated guanylate kinase (MAGUK) family of proteins, members of which can serve as scaffolds to organize signaling complexes. Cher is related to actin filament cross-linking proteins that regulate actin cytoskeleton dynamics. The PDZ domain binding motif found in the most C-terminal region of the Sema-1a ICD is necessary for interaction with Vari, but not Cher, indicative of distinct binding modalities. Pbl/Sema-1a-mediated repulsive guidance is potentiated by both and Genetic analyses further suggest that scaffolding functions of Vari and Cher play an important role in Pbl-mediated Sema-1a reverse signaling. These results define intracellular components critical for signal transduction from the Sema-1a receptor to the cytoskeleton and provide insight into mechanisms underlying semaphorin-induced localized changes in cytoskeletal organization.
跨膜信号素 Sema-1a 既能作为配体又能作为受体，在神经发育过程中调节轴突-轴突排斥。Pebble（Pbl）是一种 Rho 鸟嘌呤核苷酸交换因子，通过与 Sema-1a 细胞内结构域（ICD）的 N 端区域结合，介导 Sema-1a 反向信号，导致细胞骨架重排。在这里，我们发现了另外两个 Sema-1a 相互作用的蛋白，vari 和 cheerio，它们都具有神经元功能，是运动轴突寻路所必需的。Vari 是膜相关鸟苷酸激酶（MAGUK）家族蛋白的成员，该家族成员可以作为支架来组织信号复合物。Cher 与肌动蛋白丝交联蛋白有关，后者调节肌动蛋白细胞骨架动力学。在 Sema-1a ICD 的最 C 端区域发现的 PDZ 结构域结合基序是与 Vari 相互作用所必需的，但不是与 Cher 相互作用所必需的，表明了不同的结合模式。Pbl/Sema-1a 介导的排斥性导向作用被 和 增强。遗传分析进一步表明，Vari 和 Cher 的支架功能在 Pbl 介导的 Sema-1a 反向信号中起着重要作用。这些结果定义了从 Sema-1a 受体到细胞骨架的信号转导的关键细胞内成分，并为 semaphorin 诱导的细胞骨架组织局部变化的机制提供了深入了解。
