University of Lyon, University Claude Bernard Lyon 1, CGphiMC UMR CNRS 5534, Lyon, France.
Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Nat Neurosci. 2015 Jan;18(1):36-45. doi: 10.1038/nn.3893. Epub 2014 Dec 8.
Robo-Slit and Plexin-Semaphorin signaling participate in various developmental and pathogenic processes. During commissural axon guidance in the spinal cord, chemorepulsion by Semaphorin3B and Slits controls midline crossing. Slit processing generates an N-terminal fragment (SlitN) that binds to Robo1 and Robo2 receptors and mediates Slit repulsive activity, as well as a C-terminal fragment (SlitC) with an unknown receptor and bioactivity. We identified PlexinA1 as a Slit receptor and found that it binds the C-terminal Slit fragment specifically and transduces a SlitC signal independently of the Robos and the Neuropilins. PlexinA1-SlitC complexes are detected in spinal cord extracts, and ex vivo, SlitC binding to PlexinA1 elicits a repulsive commissural response. Analysis of various ligand and receptor knockout mice shows that PlexinA1-Slit and Robo-Slit signaling have complementary roles during commissural axon guidance. Thus, PlexinA1 mediates both Semaphorin and Slit signaling, and Slit processing generates two active fragments, each exerting distinct effects through specific receptors.
Robo-Slit 和 Plexin-Semaphorin 信号参与各种发育和发病过程。在脊髓的联络轴突导向中，Semaphorin3B 和 Slits 的化学排斥作用控制中线交叉。Slit 的加工产生一个 N 端片段（SlitN），与 Robo1 和 Robo2 受体结合，并介导 Slit 的排斥活性，以及一个具有未知受体和生物活性的 C 端片段（SlitC）。我们确定了 PlexinA1 是 Slit 的受体，并发现它特异性地结合 C 端 Slit 片段，并独立于 Robos 和 Neuropilins 转导 SlitC 信号。在脊髓提取物中检测到 PlexinA1-SlitC 复合物，并且在体外，SlitC 与 PlexinA1 的结合引发排斥性联络反应。对各种配体和受体敲除小鼠的分析表明，PlexinA1-Slit 和 Robo-Slit 信号在联络轴突导向中具有互补作用。因此，PlexinA1 介导 Semaphorin 和 Slit 信号，Slit 的加工产生两个活性片段，每个片段通过特定受体发挥不同的作用。
