Department of Neuroscience, University of Pennsylvania School of Medicine, 1113 BRB2/3, 421 Curie Boulevard, Philadelphia, PA 19104, USA.
Development. 2010 Jul;137(14):2417-26. doi: 10.1242/dev.047993.
Slits and their Roundabout (Robo) receptors mediate repulsive axon guidance at the Drosophila ventral midline and in the vertebrate spinal cord. Slit is cleaved to produce fragments with distinct signaling properties. In a screen for genes involved in Slit-Robo repulsion, we have identified the Adam family metalloprotease Kuzbanian (Kuz). Kuz does not regulate midline repulsion through cleavage of Slit, nor is Slit cleavage essential for repulsion. Instead, Kuz acts in neurons to regulate repulsion and Kuz can cleave the Robo extracellular domain in Drosophila cells. Genetic rescue experiments using an uncleavable form of Robo show that this receptor does not maintain normal repellent activity. Finally, Kuz activity is required for Robo to recruit its downstream signaling partner, Son of sevenless (Sos). These observations support the model that Kuz-directed cleavage is important for Robo receptor activation.
裂缝及其绕路 (Robo) 受体在果蝇腹侧中线和脊椎动物脊髓中介导排斥性轴突导向。裂缝被切割产生具有不同信号特性的片段。在筛选参与 Slit-Robo 排斥的基因时，我们已经鉴定出 Adam 家族金属蛋白酶 Kuzbanian (Kuz)。Kuz 不通过 Slit 的切割来调节中线排斥，Slit 的切割对于排斥也不是必需的。相反，Kuz 在神经元中起作用以调节排斥，并且 Kuz 可以在果蝇细胞中切割 Robo 细胞外结构域。使用不可切割形式的 Robo 的遗传挽救实验表明，这种受体不能维持正常的排斥活性。最后，Kuz 的活性对于 Robo 招募其下游信号伙伴 Son of sevenless (Sos) 是必需的。这些观察结果支持这样的模型，即 Kuz 定向切割对于 Robo 受体的激活很重要。
