一种人类DCC变异导致镜像运动障碍，揭示WAVE调控复合物介导Netrin-1-DCC的轴突引导机制

A human DCC variant causing mirror movement disorder reveals that the WAVE regulatory complex mediates axon guidance by netrin-1-DCC

Science Signaling

影响因子:6.6

分区:生物学1区 Top / 生化与分子生物学2区细胞生物学2区

发表日期:2024 Oct

作者: Karina Chaudhari, Kaiyue Zhang, Patricia T Yam, Yixin Zang, Daniel A Kramer, Sarah Gagnon, Sabrina Schlienger, Sara Calabretta, Jean-Francois Michaud, Meagan Collins, Junmei Wang, Myriam Srour, Baoyu Chen, Frédéric Charron, Greg J Bashaw

DOI: 10.1126/scisignal.adk2345

摘要

轴突引导信号分子Netrin-1通过其受体DCC（结直肠癌中的缺失基因）引导交叉神经轴突向中线迁移。DCC的变异常常与先天性镜像运动（CMM）相关。一个与CMM相关的变异位于DCC胞质尾的保守基序中，该基序被预测为与调控肌动蛋白动力学的WAVE（Wiskott-Aldrich综合征蛋白家族蛋白）调控复合物（WRC）结合。在本研究中，我们探讨了此变异如何影响DCC功能及其在CMM中的潜在作用。我们发现，DCC胞质尾中的一个保守的WRC相互作用受体序列（WIRS）基序介导了DCC与WRC的相互作用。这一相互作用对于体外培养的啮齿动物交叉神经元中Netrin-1介导的轴突引导是必要的。此外，果蝇DCC的同源蛋白Fra中的WIRS基序在果蝇中线的吸引信号中也具有必要性。DCC的R1343H变异（与CMM相关）改变了WIRS基序，阻断了DCC与WRC的相互作用，并在体外交叉神经元和果蝇中损害了轴突引导。这些发现揭示了WRC作为Netrin-1-DCC信号传导的重要组成部分，并阐明了人类遗传变异在DCC胞质尾可能导致CMM的分子机制。

Abstract

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.