Takegahara Noriko, Takamatsu Hyota, Toyofuku Toshihiko, Tsujimura Tohru, Okuno Tatsusada, Yukawa Kazunori, Mizui Masayuki, Yamamoto Midori, Prasad Durbaka V R, Suzuki Kazuhiro, Ishii Masaru, Terai Kenta, Moriya Masayuki, Nakatsuji Yuji, Sakoda Saburo, Sato Shintaro, Akira Shizuo, Takeda Kiyoshi, Inui Masanori, Takai Toshiyuki, Ikawa Masahito, Okabe Masaru, Kumanogoh Atsushi, Kikutani Hitoshi
Department of Molecular Immunology and CREST program of JST, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
Nat Cell Biol. 2006 Jun;8(6):615-22. doi: 10.1038/ncb1416. Epub 2006 May 21.
Semaphorins and their receptors have diverse functions in axon guidance, organogenesis, vascularization and/or angiogenesis, oncogenesis and regulation of immune responses. The primary receptors for semaphorins are members of the plexin family. In particular, plexin-A1, together with ligand-binding neuropilins, transduces repulsive axon guidance signals for soluble class III semaphorins, whereas plexin-A1 has multiple functions in chick cardiogenesis as a receptor for the transmembrane semaphorin, Sema6D, independent of neuropilins. Additionally, plexin-A1 has been implicated in dendritic cell function in the immune system. However, the role of plexin-A1 in vivo, and the mechanisms underlying its pleiotropic functions, remain unclear. Here, we generated plexin-A1-deficient (plexin-A1(-/-)) mice and identified its important roles, not only in immune responses, but also in bone homeostasis. Furthermore, we show that plexin-A1 associates with the triggering receptor expressed on myeloid cells-2 (Trem-2), linking semaphorin-signalling to the immuno-receptor tyrosine-based activation motif (ITAM)-bearing adaptor protein, DAP12. These findings reveal an unexpected role for plexin-A1 and present a novel signalling mechanism for exerting the pleiotropic functions of semaphorins.
信号素及其受体在轴突导向、器官发生、血管形成和/或血管生成、肿瘤发生以及免疫反应调节中具有多种功能。信号素的主要受体是丛状蛋白家族的成员。特别是，丛状蛋白-A1与配体结合的神经纤毛蛋白一起，转导可溶性III类信号素的排斥性轴突导向信号，而丛状蛋白-A1在鸡心脏发生中作为跨膜信号素Sema6D的受体具有多种功能，与神经纤毛蛋白无关。此外，丛状蛋白-A1与免疫系统中树突状细胞的功能有关。然而，丛状蛋白-A1在体内的作用及其多效性功能的潜在机制仍不清楚。在这里，我们生成了丛状蛋白-A1缺陷（plexin-A1(-/-)）小鼠，并确定了其重要作用，不仅在免疫反应中，而且在骨稳态中。此外，我们表明丛状蛋白-A1与髓系细胞上表达的触发受体-2（Trem-2）相关联，将信号素信号传导与基于免疫受体酪氨酸的激活基序（ITAM）的衔接蛋白DAP12联系起来。这些发现揭示了丛状蛋白-A1的意外作用，并提出了一种新的信号传导机制来发挥信号素的多效性功能。
