Balancing of ephrin/Eph forward and reverse signaling as the driving force of adaptive topographic mapping
Balancing of ephrin/Eph forward and reverse signaling as the driving force of adaptive topographic mapping
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DOI：
10.1242/dev.070474
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发表时间：
2012-01-15
期刊：
影响因子：
4.6
通讯作者：
Weth, Franco
中科院分区：
文献类型：
--
作者：
Gebhardt, Christoph;Bastmeyer, Martin;Weth, Franco
视网膜顶盖投射是将视网膜轴突映射到中脑顶盖上的一种拓扑学结构，是研究胚胎脑布线的分子遗传学的理想模型系统。证实Sperry的精液假说，肝配蛋白/Eph反梯度的视网膜和顶盖被发现代表匹配的化学特异性标志物。然而，有趣的是，用这些线索在体外重建拓扑学上合适的纤维生长是不可能的。此外，实验衍生的分子机制未能提供解释，为什么映射适应在一些实验中的各种目标，而在其他显示严格的点对点的特异性。在体外，肝配蛋白-A/EphA正向和反向信号传导介导对视网膜纤维的差异排斥，而不是提供地形引导。我们认为，这些反应表明肝配蛋白-A和EphA是一个指导系统，需要两个抵消线索每轴的成员。在实验中，我们证明，通过引入新的双线索条纹检测，同时存在的两个线索确实足以引起地形适当的指导。这种独特的机制通过单一受体/配体组合使用正向和反向信号，需要纤维/纤维相互作用。因此，我们建议扩展Sperry的模型，包括肝配蛋白-A/EphA为基础的纤维/纤维化学特异性，最终竞争的纤维/目标相互作用。通过计算机模拟，我们表明，我们的模型是一致的条纹实验结果。然而，更重要的是，它不仅解释了点对点和自适应地形图绘制的经典体内证据，而且还解释了在视网膜EphA敲入小鼠中发现的图复制。尽管如此，它是基于地形生长锥导航的单一约束：肝配蛋白-A/EphA正向和反向信号传导的平衡。
The retinotectal projection, which topographically maps retinal axons onto the tectum of the midbrain, is an ideal model system with which to investigate the molecular genetics of embryonic brain wiring. Corroborating Sperry's seminal hypothesis, ephrin/Eph counter-gradients on both retina and tectum were found to represent matching chemospecificity markers. Intriguingly, however, it has never been possible to reconstitute topographically appropriate fiber growth in vitro with these cues. Moreover, experimentally derived molecular mechanisms have failed to provide explanations as to why the mapping adapts to grossly diverse targets in some experiments, while displaying strict point-to-point specificity in others. In vitro, ephrin-A/EphA forward, as well as reverse, signaling mediate differential repulsion to retinal fibers, instead of providing topographic guidance. We argue that those responses are indicative of ephrin-A and EphA being members of a guidance system that requires two counteracting cues per axis. Experimentally, we demonstrate by introducing novel double-cue stripe assays that the simultaneous presence of both cues indeed suffices to elicit topographically appropriate guidance. The peculiar mechanism, which uses forward and reverse signaling through a single receptor/ligand combination, entails fiber/fiber interactions. We therefore propose to extend Sperry's model to include ephrin-A/EphA-based fiber/fiber chemospecificity, eventually out-competing fiber/target interactions. By computational simulation, we show that our model is consistent with stripe assay results. More importantly, however, it not only accounts for classical in vivo evidence of point-to-point and adaptive topographic mapping, but also for the map duplication found in retinal EphA knock-in mice. Nonetheless, it is based on a single constraint of topographic growth cone navigation: the balancing of ephrin-A/EphA forward and reverse signaling.