Genetic analysis of EphA-dependent signaling mechanisms controlling topographic mapping in vivo
Genetic analysis of EphA-dependent signaling mechanisms controlling topographic mapping in vivo
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DOI：
10.1242/dev.02623
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发表时间：
2006-11-15
期刊：
影响因子：
4.6
通讯作者：
Vanderhaeghen, Pierre
中科院分区：
文献类型：
--
作者：
Dufour, Audrey;Egea, Joaquim;Vanderhaeghen, Pierre
Ephrin/Eph 配体和受体因其在神经连接拓扑图绘制中的突出作用而闻名。尽管大量工作集中在各种细胞环境中的肝配蛋白/Eph 依赖性信号通路上，但 Eph 受体在神经映射中的作用分子机制（需要肝配蛋白和 Eph 受体的互补梯度之间的动态相互作用）仍然很大程度上未知。在这里，我们在体内研究了由 EphA4 受体介导的神经映射的信号传导机制，先前已证明该受体可以控制小鼠体感系统中丘脑皮质轴突的拓扑特异性。通过对显示 Epha4 基因选择性突变的敲入小鼠系进行轴突追踪分析，我们首次确定了地形图绘制所需的 Eph 受体的哪些细胞内结构域。我们提供了直接的体内证据，证明 EphA4 的酪氨酸激酶结构域及其活性的严格调节是丘脑皮质轴突拓扑图绘制所必需的，而非催化功能模块，例如 PDZ 结合基序 (PBM) 和无菌 α 基序 (SAM) 结构域是可有可无的。这些数据为地形图的分子机制提供了新的见解，并构成了解析所涉及的下游信号级联的生理框架。
Ephrin/Eph ligands and receptors are best known for their prominent role in topographic mapping of neural connectivity. Despite the large amount of work centered on ephrin/Eph-dependent signaling pathways in various cellular contexts, the molecular mechanisms of action of Eph receptors in neural mapping, requiring dynamic interactions between complementary gradients of ephrins and Eph receptors, remain largely unknown. Here, we investigated in vivo the signaling mechanisms of neural mapping mediated by the EphA4 receptor, previously shown to control topographic specificity of thalamocortical axons in the mouse somatosensory system. Using axon tracing analyses of knock-in mouse lines displaying selective mutations for the Epha4 gene, we determined for the first time which intracellular domains of an Eph receptor are required for topographic mapping. We provide direct in vivo evidence that the tyrosine kinase domain of EphA4, as well as a tight regulation of its activity, are required for topographic mapping of thalamocortical axons, whereas non-catalytic functional modules, such as the PDZ-binding motif (PBM) and the Sterile-alpha motif (SAM) domain, are dispensable. These data provide a novel insight into the molecular mechanisms of topographic mapping, and constitute a physiological framework for the dissection of the downstream signaling cascades involved.