Plexin-A1 and its interaction with DAP12 in immune responses and bone homeostasis
Plexin-A1 and its interaction with DAP12 in immune responses and bone homeostasis
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DOI：
10.1038/ncb1416
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发表时间：
2006-06-01
影响因子：
21.3
通讯作者：
Kikutani, Hitoshi
中科院分区：
文献类型：
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作者：
Takegahara, Noriko;Takamatsu, Hyota;Kikutani, Hitoshi
信号素及其受体在轴突引导、器官发生、血管形成和/或血管生成、肿瘤形成和免疫反应调节中具有不同的功能(1-11)。信号素的主要受体是丛状蛋白家族的成员(2，12-14)。特别是，Plexin-A1与配体结合的神经毛平蛋白一起传递可溶的III类信号素的排斥性轴突引导信号(15)，而Plexin-A1作为跨膜信号素Sema6D的受体在鸡心脏发生中具有多种功能，而不依赖神经毛平蛋白(16)。此外，丛状蛋白-A1还与免疫系统中的树突状细胞功能有关(17)。然而，丛状蛋白-A1在体内的作用以及其多效性功能的潜在机制仍不清楚。在这里，我们产生了Plexin-A1缺陷(Plexin-A1(-/-))小鼠，并确定了它不仅在免疫反应中的重要作用，而且在骨骼稳态中也发挥了重要作用。此外，我们发现丛蛋白-A1与髓样细胞上表达的触发受体-2(TREM2)有关，将信号素信号与免疫受体酪氨酸激活基序(ITAM)适配器蛋白DAP12联系起来。这些发现揭示了丛状蛋白-A1的一个意想不到的作用，并提出了一种新的信号机制来发挥信号素的多效性功能。
Semaphorins and their receptors have diverse functions in axon guidance, organogenesis, vascularization and/or angiogenesis, oncogenesis and regulation of immune responses(1-11). The primary receptors for semaphorins are members of the plexin family(2,12-14). In particular, plexin-A1, together with ligand-binding neuropilins, transduces repulsive axon guidance signals for soluble class III semaphorins(15), whereas plexin-A1 has multiple functions in chick cardiogenesis as a receptor for the transmembrane semaphorin, Sema6D, independent of neuropilins(16). Additionally, plexin-A1 has been implicated in dendritic cell function in the immune system(17). 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 (Trem2), 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.