Dalloz Cécile, Sarig Rachel, Fort Patrice, Yaffe David, Bordais Agnès, Pannicke Thomas, Grosche Jens, Mornet Dominique, Reichenbach Andreas, Sahel José, Nudel Uri, Rendon Alvaro
INSERM U-592, Laboratoire de Physiopathologie Cellulaire et Moléculaire de la Rétine, Hôpital Saint-Antoine, Bâtiment Kourilsky, 6ème étage, 184 rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France.
Hum Mol Genet. 2003 Jul 1;12(13):1543-54. doi: 10.1093/hmg/ddg170.
The abnormal retinal neurotransmission observed in Duchenne muscular dystrophy (DMD) patients and in some genotypes of mice lacking dystrophin has been attributed to altered expression of short products of the dystrophin gene. We have investigated the potential role of Dp71, the most abundant C-terminal dystrophin gene product, in retinal electrophysiology. Comparison of the scotopic electroretinograms (ERG) between Dp71-null mice and wild-type (wt) littermates revealed a normal ERG in Dp71-null mice with no significant changes of the b-wave amplitude and kinetics. Analysis of DMD gene products, utrophin and dystrophin-associated proteins (DAPs), showed that Dp71 and utrophin were localized around the blood vessels, in the ganglion cell layer (GCL), and the inner limiting membrane (ILM). Dp71 deficiency was accompanied by an increased level of utrophin and decreased level of beta-dystroglycan localized in the ILM, without any apparent effect on the other DAPs. Dp71 deficiency was also associated with an impaired clustering of two Müller glial cell proteins-the inwardly rectifying potassium channel Kir4.1 and the water pore aquaporin 4 (AQP4). Immunostaining of both proteins decreased around blood vessels and in the ILM of Dp71-null mice, suggesting that Dp71 plays a role in the clustering and/or stabilization of the two proteins. AQP4 and Kir4.1 may also be involved in the regulation of the ischemic process. We found that a transient ischemia resulted in a greater damage in the GCL of mice lacking Dp71 than in wt mice. This finding points at a crucial role played by Dp71 in retinal function.
在杜兴氏肌营养不良症（DMD）患者以及一些缺乏肌营养不良蛋白的小鼠基因型中观察到的视网膜神经传递异常，被归因于肌营养不良蛋白基因短产物的表达改变。我们研究了肌营养不良蛋白基因最丰富的C末端产物Dp71在视网膜电生理学中的潜在作用。比较Dp71基因敲除小鼠和野生型（wt）同窝小鼠的暗视视网膜电图（ERG）发现，Dp71基因敲除小鼠的ERG正常，b波振幅和动力学无显著变化。对DMD基因产物、抗肌萎缩蛋白聚糖和肌营养不良蛋白相关蛋白（DAPs）的分析表明，Dp71和抗肌萎缩蛋白聚糖定位于血管周围、神经节细胞层（GCL）和内界膜（ILM）。Dp71缺乏伴随着抗肌萎缩蛋白聚糖水平的升高和定位于ILM的β-肌营养不良聚糖水平的降低，而对其他DAPs没有明显影响。Dp71缺乏还与两种穆勒胶质细胞蛋白——内向整流钾通道Kir4.1和水通道蛋白4（AQP4）的聚集受损有关。在Dp71基因敲除小鼠的血管周围和ILM中，这两种蛋白的免疫染色均减少，表明Dp71在这两种蛋白的聚集和/或稳定中发挥作用。AQP4和Kir4.1也可能参与缺血过程的调节。我们发现，短暂缺血对缺乏Dp71的小鼠GCL造成的损伤比对wt小鼠造成的损伤更大。这一发现表明Dp71在视网膜功能中起着关键作用。
