The Actin-Binding Protein Canoe/AF-6 Forms a Complex with Robo and Is Required for Slit-Robo Signaling during Axon Pathfinding at the CNS Midline
The Actin-Binding Protein Canoe/AF-6 Forms a Complex with Robo and Is Required for Slit-Robo Signaling during Axon Pathfinding at the CNS Midline
复制标题
肌动蛋白结合蛋白 Canoe/AF-6 与 Robo 形成复合物，是中枢神经系统中线轴突寻路过程中 Slit-Robo 信号传导所必需的
DOI：
10.1523/jneurosci.6342-11.2012
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
A. Carmena
中科院分区：
文献类型：
--
作者：
J. Slováková;S. Speicher;N. Sánchez;A. Prokop;A. Carmena
轴突导向是神经系统发育和再生的关键过程。研究这一过程的机制的最佳范例之一是轴突决定是否穿过果蝇中枢神经系统的中线。这一决定的一个重要调节因子是高度保守的Slit-Robo信号通路。狭缝引导线索通过Robo受体起作用以排斥来自中线的轴突。尽管我们对这些蛋白质的了解取得了很大进展，但与Robo功能相关的细胞内机制仍然不清楚。在这项工作中，我们发现支架蛋白Canoe（Cno），AF-6/Afadin的果蝇直向同源物，是Slit-Robo信号传导所必需的。Cno表达沿着纵向轴突先驱束，纵向Robo/Fasciclin 2阳性轴突异常地穿过cno突变胚胎的中线。cno突变的原代神经元显示出定位于生长锥丝状伪足中的Robo的显著减少，并且Cno在体内与Robo形成复合物。此外，无连合（commissuerless，CCN）表型（即，由于在所有神经元中Robo的组成性表面呈递而缺乏连合），在CNO、CNO双突变胚胎中受到抑制。cno、slit、robo和编码Robo途径的其他组分的基因（例如Neurexin-IV、Syndecan和Rac GTP酶）之间的特定遗传相互作用进一步证实了Cno在功能上与Slit-Robo途径相互作用。我们的数据表明，Cno是Slit-Robo信号通路的一种新型调节剂，对于调节Robo的亚细胞定位和在中线轴突引导期间将其信号转导到肌动蛋白细胞骨架至关重要。
Axon guidance is a key process during nervous system development and regeneration. One of the best established paradigms to study the mechanisms underlying this process is the axon decision of whether or not to cross the midline in the Drosophila CNS. An essential regulator of that decision is the well conserved Slit-Robo signaling pathway. Slit guidance cues act through Robo receptors to repel axons from the midline. Despite good progress in our knowledge about these proteins, the intracellular mechanisms associated with Robo function remain poorly defined. In this work, we found that the scaffolding protein Canoe (Cno), the Drosophila orthologue of AF-6/Afadin, is essential for Slit-Robo signaling. Cno is expressed along longitudinal axonal pioneer tracts, and longitudinal Robo/Fasciclin2-positive axons aberrantly cross the midline in cno mutant embryos. cno mutant primary neurons show a significant reduction of Robo localized in growth cone filopodia and Cno forms a complex with Robo in vivo. Moreover, the commissureless (comm) phenotype (i.e., lack of commissures due to constitutive surface presentation of Robo in all neurons) is suppressed in comm, cno double-mutant embryos. Specific genetic interactions between cno, slit, robo, and genes encoding other components of the Robo pathway, such as Neurexin-IV, Syndecan, and Rac GTPases, further confirm that Cno functionally interacts with the Slit-Robo pathway. Our data argue that Cno is a novel regulator of the Slit-Robo signaling pathway, crucial for regulating the subcellular localization of Robo and for transducing its signaling to the actin cytoskeleton during axon guidance at the midline.
影响因子：
7.2
作者：
Bashaw, Greg J.;Klein, Ruediger
通讯作者：
Klein, Ruediger
影响因子：
13.9
作者：
O'Donnell M;Chance RK;Bashaw GJ
通讯作者：
Bashaw GJ
影响因子：
4.6
作者：
M. Georgiou;G. Tear
通讯作者：
M. Georgiou;G. Tear