轴突引导信号 netrin-1 通过其受体 DCC（在结直肠癌中缺失）发出信号，将连合轴突吸引到中线。 DCC 的变异通常与先天性镜像运动 (CMM) 有关。 DCC 细胞质尾部的 CMM 相关变体位于保守基序中，预计与肌动蛋白动力学调节因子 WAVE（Wiskott-Aldrich 综合征蛋白家族维普林同源蛋白）调节复合物 (WRC) 结合。在这里，我们探讨了这种变异如何影响 DCC 功能并可能对 CMM 做出贡献。我们发现 DCC 细胞质尾部保守的 WRC 相互作用受体序列 (WIRS) 基序介导 DCC 和 WRC 之间的相互作用。这种相互作用对于培养的啮齿动物连合神经元中 netrin-1 介导的轴突引导是必需的。此外，果蝇 DCC 直向同源物 Fra 的 WIRS 基序是果蝇中线体内有吸引力的信号传导所必需的。 DCC 的 CMM 相关 R1343H 变体改变了 WIRS 基序，阻止了 DCC-WRC 相互作用，并损害了培养的连合神经元和果蝇中的轴突引导。研究结果揭示了 WRC 是 netrin-1-DCC 信号传导的关键组成部分，并揭示了一种分子机制，解释了 DCC 细胞质尾部的人类遗传变异如何导致 CMM。

The axon guidance cue netrin-1 signals through its receptor DCC (deleted in colorectal cancer) to attract commissural axons to the midline. Variants in DCC are frequently associated with congenital mirror movements (CMMs). A CMM-associated variant in the cytoplasmic tail of DCC is located in a conserved motif predicted to bind to a regulator of actin dynamics called the WAVE (Wiskott-Aldrich syndrome protein-family verprolin homologous protein) regulatory complex (WRC). Here, we explored how this variant affects DCC function and may contribute to CMM. We found that a conserved WRC-interacting receptor sequence (WIRS) motif in the cytoplasmic tail of DCC mediated the interaction between DCC and the WRC. This interaction was required for netrin-1-mediated axon guidance in cultured rodent commissural neurons. Furthermore, the WIRS motif of Fra, the Drosophila DCC ortholog, was required for attractive signaling in vivo at the Drosophila midline. The CMM-associated R1343H variant of DCC, which altered the WIRS motif, prevented the DCC-WRC interaction and impaired axon guidance in cultured commissural neurons and in Drosophila. The findings reveal the WRC as a pivotal component of netrin-1-DCC signaling and uncover a molecular mechanism explaining how a human genetic variant in the cytoplasmic tail of DCC may lead to CMM.