PDF(Sci-hub)
Abstract：
Progressive rod-cone degeneration (PRCD) is a small protein residing in the light-sensitive disc membranes of the photoreceptor outer segment. Until now, the function of PRCD has remained enigmatic despite multiple demonstrations that its mutations cause blindness in humans and dogs. Here, we generated a PRCD knockout mouse and observed a striking defect in disc morphogenesis, whereby newly forming discs do not properly flatten. This leads to the budding of disc-derived vesicles, specifically at the site of disc morphogenesis, which accumulate in the interphotoreceptor matrix. The defect in nascent disc flattening only minimally alters the photoreceptor outer segment architecture beyond the site of new disc formation and does not affect the abundance of outer segment proteins and the photoreceptor\'s ability to generate responses to light. Interestingly, the retinal pigment epithelium, responsible for normal phagocytosis of shed outer segment material, lacks the capacity to clear the disc-derived vesicles. This deficiency is partially compensated by a unique pattern of microglial migration to the site of disc formation where they actively phagocytize vesicles. However, the microglial response is insufficient to prevent vesicular accumulation and photoreceptors of PRCD knockout mice undergo slow, progressive degeneration. Taken together, these data show that the function of PRCD is to keep evaginating membranes of new discs tightly apposed to each other, which is essential for the high fidelity of photoreceptor disc morphogenesis and photoreceptor survival.
摘要：
进行性视锥退变（PRCD）是一种小蛋白质，存在于感光体外段的光敏椎间盘膜中。直到现在,尽管多次证明PRCD的突变会导致人和犬失明,但PRCD的功能仍然是个谜.这里,我们产生了PRCD敲除小鼠，并观察到椎间盘形态发生的惊人缺陷，由此新形成的圆盘不能适当变平。这导致椎间盘衍生的囊泡出芽，特别是在椎间盘形态发生的部位，在光感受器间基质中积累。新生椎间盘平坦化的缺陷仅最小程度地改变了新椎间盘形成部位以外的感光体外段结构，并且不影响外段蛋白的丰度和感光体对光产生响应的能力。有趣的是,视网膜色素上皮，负责脱落的外节材料的正常吞噬作用，缺乏清除椎间盘衍生囊泡的能力。这种缺陷被小胶质细胞迁移到椎间盘形成部位的独特模式部分补偿，在那里它们主动吞噬囊泡。然而,小胶质细胞反应不足以防止PRCD敲除小鼠的囊泡积累和光感受器经历缓慢，进行性退化。一起来看,这些数据表明，PRCD的功能是保持新圆盘的逃逸膜紧密贴合，这对于光感受器盘形态发生和光感受器存活的高保真度至关重要。
