引起镜像运动障碍的人类DCC变体揭示了波调节复合物介导Netrin-1-DCC的轴突指导
A human DCC variant causing mirror movement disorder reveals that the WAVE regulatory complex mediates axon guidance by netrin-1-DCC
影响因子:6.60000
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
摘要
轴突引导提示Netrin-1通过其受体DCC（在结直肠癌中删除）的信号吸引了连锁轴突进入中线。 DCC中的变体通常与先天镜运动（CMM）相关。 DCC的细胞质尾巴中与CMM相关的变体位于一个保守的基序中，该基序被预测与称为波（Wiskott-Aldrich综合征蛋白蛋白 - 植物性垂体同源蛋白）的肌动蛋白动力学调节剂结合，调节复合物（WRC）。在这里，我们探讨了这种变体如何影响DCC功能，并可能对CMM有所帮助。我们发现，DCC的细胞质尾部中保守的WRC相互作用受体序列（WIR）基序介导了DCC与WRC之间的相互作用。这种相互作用是Netrin-1介导的轴突指导在培养的啮齿动物连合神经元中所必需的。此外，果蝇中线的体内信号传导需要FRA的WIR基序（果蝇DCC直系同源物）。 DCC的CMM相关的R1343H变体改变了WIRS基序，防止了DCC-WRC的相互作用和在培养的连锁神经元和果蝇中的轴突引导障碍。这些发现揭示了WRC是Netrin-1-DCC信号传导的关键成分，并发现了分子机制，解释了DCC细胞质尾部中的人类遗传变异如何导致CMM。
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.