MIG-10 Functions with ABI-1 to Mediate the UNC-6 and SLT-1 Axon Guidance Signaling Pathways

Extracellular guidance cues steer axons towards their targets by eliciting morphological changes in the growth cone. A key part of this process is the asymmetric recruitment of the cytoplasmic scaffolding protein MIG-10 (lamellipodin). MIG-10 is thought to asymmetrically promote outgrowth by inducing actin polymerization. However, the mechanism that links MIG-10 to actin polymerization is not known. We have identified the actin regulatory protein ABI-1 as a partner for MIG-10 that can mediate its outgrowth-promoting activity. The SH3 domain of ABI-1 binds to MIG-10, and loss of function of either of these proteins causes similar axon guidance defects. Like MIG-10, ABI-1 functions in both the attractive UNC-6 (netrin) pathway and the repulsive SLT-1 (slit) pathway. Dosage sensitive genetic interactions indicate that MIG-10 functions with ABI-1 and WVE-1 to mediate axon guidance. Epistasis analysis reveals that ABI-1 and WVE-1 function downstream of MIG-10 to mediate its outgrowth-promoting activity. Moreover, experiments with cultured mammalian cells suggest that the interaction between MIG-10 and ABI-1 mediates a conserved mechanism that promotes formation of lamellipodia. Together, these observations suggest that MIG-10 interacts with ABI-1 and WVE-1 to mediate the UNC-6 and SLT-1 guidance pathways.细胞外导向因子通过诱导生长锥产生形态变化，引导轴突向靶标方向延伸。该过程的核心环节之一，是胞质支架蛋白MIG-10（lamellipodin）的不对称募集。学界普遍认为，MIG-10可通过诱导肌动蛋白聚合，实现对轴突生长的不对称促进作用。然而，将MIG-10与肌动蛋白聚合过程相偶联的具体分子机制仍未阐明。本研究鉴定出肌动蛋白调节蛋白ABI-1可作为MIG-10的结合伴侣，介导其促轴突生长的活性。ABI-1的SH3结构域可与MIG-10结合，且二者任一蛋白的功能缺失都会引发表型相似的轴突导向缺陷。与MIG-10类似，ABI-1同时参与吸引性UNC-6（netrin）通路与排斥性SLT-1（slit）通路的调控。剂量敏感型遗传互作实验结果显示，MIG-10与ABI-1、WVE-1协同参与轴突导向的调控过程。上位性分析结果表明，ABI-1与WVE-1作用于MIG-10的下游，介导其促轴突生长的活性。此外，基于培养哺乳动物细胞的实验结果提示，MIG-10与ABI-1的相互作用，介导了一套保守的、可促进片状伪足形成的分子机制。综上，上述实验结果表明，MIG-10通过与ABI-1及WVE-1相互作用，调控UNC-6与SLT-1介导的轴突导向通路。