p75(NTR) mediates ephrin-A reverse signaling required for axon repulsion and mapping.
p75(NTR) mediates ephrin-A reverse signaling required for axon repulsion and mapping.
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DOI：
10.1016/j.neuron.2008.07.032
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发表时间：
2008-09-11
期刊：
影响因子：
16.2
通讯作者：
O'Leary DD
中科院分区：
文献类型：
--
作者：
Lim YS;McLaughlin T;Sung TC;Santiago A;Lee KF;O'Leary DD
肝配蛋白-As在结合EphAs后的反向信号传导控制轴突引导和映射。Ephrin-As是GPI锚定到膜上，需要它们与抑制其信号的跨膜蛋白复合。我们发现，p75神经营养因子受体（NTR）在视网膜轴突中发挥这一作用。p75 NTR和肝配蛋白-A共定位于沿着视网膜轴突的小窝内，并在结合EphAs时形成Fyn磷酸化所需的复合物，激活导致细胞骨架变化的信号传导途径。在体外，通过ephrin-A反向信号传导的视网膜轴突对EphAs的排斥需要p75 NTR，但通过EphA正向信号传导的对ephrin-As的排斥不需要。组成型和视网膜特异性p75 NTR敲除小鼠在上级丘的视网膜轴突末端存在异常前移，这与分级丘EphAs诱导的分级肝配蛋白A反向信号传导介导的排斥活性减弱一致。我们的结论是，p75 NTR是一个信号伴侣ephrin-As和ephrin-A-p75 NTR复合物的反向信号，以介导轴突排斥所需的指导和映射。
Reverse signaling by ephrin-As upon binding EphAs controls axon guidance and mapping. Ephrin-As are GPI-anchored to the membrane, requiring that they complex with transmembrane proteins that transduce their signals. We show that the p75 neurotrophin receptor (NTR) serves this role in retinal axons. p75NTR and ephrin-A co-localize within caveolae along retinal axons and form a complex required for Fyn phosphorylation upon binding EphAs, activating a signaling pathway leading to cytoskeletal changes. In vitro, retinal axon repulsion to EphAs by ephrin-A reverse signaling requires p75NTR but repulsion to ephrin-As by EphA forward signaling does not. Constitutive and retina-specific p75NTR knockout mice have aberrant anterior shifts in retinal axon terminations in superior colliculus, consistent with diminished repellent activity mediated by graded ephrin-A reverse signaling induced by graded collicular EphAs. We conclude that p75NTR is a signaling partner for ephrin-As and the ephrin-A- p75NTR complex reverse signals to mediate axon repulsion required for guidance and mapping.
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