Presynaptic Dystroglycan-Pikachurin Complex Regulates the Proper Synaptic Connection between Retinal Photoreceptor and Bipolar Cells
Presynaptic Dystroglycan-Pikachurin Complex Regulates the Proper Synaptic Connection between Retinal Photoreceptor and Bipolar Cells
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DOI：
10.1523/jneurosci.0322-12.2012
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发表时间：
2012-05-02
影响因子：
5.3
通讯作者：
Furukawa, Takahisa
中科院分区：
文献类型：
--
作者：
Omori, Yoshihiro;Araki, Fumiyuki;Furukawa, Takahisa
抗肌营养不良蛋白聚糖(DG)是突触后神经肌肉接头处抗肌营养不良蛋白-糖蛋白复合体(DGC)的重要组成部分。在小鼠视网膜中，DGC定位于光感受器细胞的突触前，但对突触前DGC的功能知之甚少。在这里，我们培育和分析了视网膜光感受器特异性DG条件性基因敲除(DG CKO)小鼠。我们发现DG CKO视网膜表现出ERG b波的波幅降低和潜伏期延长。电子显微镜分析显示，在DG CKO视网膜中，双极树突内陷到光感受器终末受到干扰。在DG CKO视网膜中，光感受器突触处的DG配体Pikachurin显著减少。有趣的是，在Pikachurin(-/-)视网膜，带状突触末端的DG信号严重减少，这表明Pikachurin是光感受器突触末端DG在突触前积累所必需的，反过来，DG也是Pikachurin积累所必需的。此外，我们还发现，皮卡丘林的过表达诱导了DG-皮卡丘林复合体在细胞表面的形成和聚集。Pigachurin的层粘连蛋白G重复序列是其齐聚和与DG相互作用的关键，也是DG-Pikachurin复合体聚集的关键。这些结果表明，Pkachurin的寡聚及其与DG的相互作用导致DG在光感受器突触终末的突触表面组装。我们的结果表明，皮卡丘林与光感受器末端的DG的突触前相互作用对于形成正确的光感受器带突触结构和正常的视网膜电生理都是必不可少的。
Dystroglycan (DG) is a key component of the dystrophin-glycoprotein complex (DGC) at the neuromuscular junction postsynapse. In the mouse retina, the DGC is localized at the presynapse of photoreceptor cells, however, the function of presynaptic DGC is poorly understood. Here, we developed and analyzed retinal photoreceptor-specific DG conditional knock-out (DG CKO) mice. We found that the DG CKO retina showed a reduced amplitude and a prolonged implicit time of the ERG b-wave. Electron microscopic analysis revealed that bipolar dendrite invagination into the photoreceptor terminus is perturbed in the DG CKO retina. In the DG CKO retina, pikachurin, a DG ligand in the retina, is markedly decreased at photoreceptor synapses. Interestingly, in the Pikachurin(-/-) retina, the DG signal at the ribbon synaptic terminus was severely reduced, suggesting that pikachurin is required for the presynaptic accumulation of DG at the photoreceptor synaptic terminus, and conversely DG is required for pikachurin accumulation. Furthermore, we found that overexpression of pikachurin induces formation and clustering of a DG-pikachurin complex on the cell surface. The Laminin G repeats of pikachurin, which are critical for its oligomerization and interaction with DG, were essential for the clustering of the DG-pikachurin complex as well. These results suggest that oligomerization of pikachurin and its interaction with DG causes DG assembly on the synapse surface of the photoreceptor synaptic terminals. Our results reveal that the presynaptic interaction of pikachurin with DG at photoreceptor terminals is essential for both the formation of proper photoreceptor ribbon synaptic structures and normal retinal electrophysiology.