MRC Centre for Developmental Neurobiology, King's College London, New Hunt's House, Guy's Campus, London SE11UL, UK.
Mol Cell Neurosci. 2011 Jun;47(2):131-6. doi: 10.1016/j.mcn.2011.03.008. Epub 2011 Apr 2.
A characteristic of the ephrin/Eph family is their capacity for bi-directional signalling. This means that an ephrin, for example, can function either as a ligand for an Eph 'receptor', or as a receptor for an Eph 'ligand'. A system in which this phenomenon is well studied is the retinotectal projection in which the guidance of retinal ganglion cell (RGC) axons to their target area in the tectum is controlled by both Ephs and ephrins expressed in gradients in both the retina and tectum. Here we have analysed the receptor function of ephrinAs on RGC axons in further detail by focussing on ephrinA6, which is the most strongly expressed ephrinA in the chick retina. EphrinAs are GPI-anchored proteins and therefore require the interaction with transmembrane proteins to exert this receptor function. Previous work has shown that ephrinAs interact on RGC axons in cis with the neurotrophin receptors p75(NTR) and TrkB. P75(NTR) then was shown to be necessary for the repulsion of ephrinA-expressing RGC axons from an EphA substrate and for the downregulation of axon branching. In turn, an interaction of ephrinAs with TrkB as well as an increase in axonal ephrinA expression augments the axon branch-promoting activity of TrkB. We now show that ephrinA6 is the necessary ephrinA component of the repulsive ephrinA/p75(NTR) receptor complex on chick RGC axons as axons lacking ephrinA6 no longer avoid an EphA matrix in stripe assay experiments. We also demonstrate that the branch-promoting activity of TrkB is dependent on ephrinA6 as a knockdown of ephrinA6 renders RGC axons insensitive to BDNF, the high affinity ligand for TrkB. In sum our data further strengthen the hypothesis that a fine-tuned interplay of ephrinAs with p75(NTR) and TrkB is important for the guidance and branching of RGC axons.
Ephrin/Eph 家族的一个特征是它们具有双向信号传递的能力。这意味着，例如，一种 Ephrin 可以作为 Eph“受体”的配体，或者作为 Eph“配体”的受体。在视网膜神经节细胞（RGC）轴突向其在顶盖中的目标区域的引导受到 Ephrin 和 Eph 在视网膜和顶盖中呈梯度表达的调控的视网膜-顶盖投射系统中，这种现象研究得很好。在这里，我们通过专注于在小鸡视网膜中表达最强的 EphrinA6，更详细地分析了 EphrinAs 在 RGC 轴突上的受体功能。EphrinAs 是 GPI 锚定蛋白，因此需要与跨膜蛋白相互作用才能发挥这种受体功能。先前的工作表明，EphrinAs 在 RGC 轴突上以顺式相互作用与神经营养因子受体 p75（NTR）和 TrkB。然后表明 p75（NTR）对于排斥表达 EphrinA 的 RGC 轴突离开 EphA 底物和下调轴突分支是必要的。反过来，EphrinAs 与 TrkB 的相互作用以及轴突 EphrinA 表达的增加增强了 TrkB 促进轴突分支的活性。我们现在表明，EphrinA6 是小鸡 RGC 轴突上排斥性 EphrinA/p75（NTR）受体复合物的必需 EphrinA 成分，因为缺乏 EphrinA6 的轴突不再在条纹测定实验中回避 EphA 基质。我们还证明了 TrkB 的分支促进活性依赖于 EphrinA6，因为 EphrinA6 的敲低使 RGC 轴突对 TrkB 的高亲和力配体 BDNF 不敏感。总之，我们的数据进一步加强了这样一种假设，即 EphrinAs 与 p75（NTR）和 TrkB 的精细相互作用对于 RGC 轴突的导向和分支很重要。
