Stein E, Tessier-Lavigne M
Department of Anatomy and Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, CA 94143, USA.
Science. 2001 Mar 9;291(5510):1928-38. doi: 10.1126/science.1058445. Epub 2001 Feb 8.
Axonal growth cones that cross the nervous system midline change their responsiveness to midline guidance cues: They become repelled by the repellent Slit and simultaneously lose responsiveness to the attractant netrin. These mutually reinforcing changes help to expel growth cones from the midline by making a once-attractive environment appear repulsive. Here, we provide evidence that these two changes are causally linked: In the growth cones of embryonic Xenopus spinal axons, activation of the Slit receptor Roundabout (Robo) silences the attractive effect of netrin-1, but not its growth-stimulatory effect, through direct binding of the cytoplasmic domain of Robo to that of the netrin receptor DCC. Biologically, this hierarchical silencing mechanism helps to prevent a tug-of-war between attractive and repulsive signals in the growth cone that might cause confusion. Molecularly, silencing is enabled by a modular and interlocking design of the cytoplasmic domains of these potentially antagonistic receptors that predetermines the outcome of their simultaneous activation.
它们会被排斥因子Slit排斥，同时失去对吸引因子netrin的反应性。这些相互强化的变化通过使曾经具有吸引力的环境变得具有排斥性，从而有助于将生长锥从中线排出。在这里，我们提供证据表明这两种变化存在因果联系：在非洲爪蟾胚胎脊髓轴突的生长锥中，Slit受体Roundabout（Robo）的激活通过Robo的细胞质结构域与netrin受体DCC的细胞质结构域直接结合，使netrin-1的吸引作用沉默，但不影响其生长刺激作用。从生物学角度来看，这种分级沉默机制有助于防止生长锥中吸引和排斥信号之间的拔河比赛，否则可能会导致混乱。从分子角度来看，沉默是由这些潜在拮抗受体的细胞质结构域的模块化和互锁设计实现的，这种设计预先决定了它们同时激活的结果。
