Lim Yoo-Shick, McLaughlin Todd, Sung Tsung-Chang, Santiago Alicia, Lee Kuo-Fen, O'Leary Dennis D M
Molecular Neurobiology Laboratory, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Neuron. 2008 Sep 11;59(5):746-58. doi: 10.1016/j.neuron.2008.07.032.
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. p75(NTR) and ephrin-A colocalize 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 p75(NTR), but repulsion to ephrin-As by EphA forward signaling does not. Constitutive and retina-specific p75(NTR) 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 p75(NTR) is a signaling partner for ephrin-As and the ephrin-A- p75(NTR) complex reverse signals to mediate axon repulsion required for guidance and mapping.
ephrin-A与EphA结合后通过反向信号传导控制轴突导向和图谱绘制。ephrin-A通过糖基磷脂酰肌醇（GPI）锚定在膜上，这就要求它们与跨膜蛋白形成复合物来转导信号。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ephrin-A沿着视网膜轴突在小窝内共定位，并在结合EphA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通路。在体外，ephrin-A反向信号传导介导的视网膜轴突对EphA的排斥需要p75（NTR），但EphA正向信号传导介导的视网膜轴突对ephrin-A的排斥则不需要。组成型和视网膜特异性p75（NTR）基因敲除小鼠的视网膜轴突在上丘的终末出现异常的向前移位，这与由上丘EphA梯度诱导的ephrin-A梯度反向信号传导介导的排斥活性降低一致。我们得出结论，p75（NTR）是ephrin-A的信号传导伙伴，ephrin-A-p75（NTR）复合物通过反向信号传导介导轴突排斥，这是导向和图谱绘制所必需的。
