Abnormal phagocytosis by retinal pigmented epithelium that lacks myosin Vila, the Usher syndrome 1B protein
Abnormal phagocytosis by retinal pigmented epithelium that lacks myosin Vila, the Usher syndrome 1B protein
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DOI：
10.1073/pnas.1130432100
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发表时间：
2003-05-27
影响因子：
11.1
通讯作者：
Williams, DS
中科院分区：
文献类型：
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作者：
Gibbs, D;Kitamoto, J;Williams, DS
肌球蛋白Vila基因(MYO7A)的突变导致了Usher综合征1B型(USH1B)，这是聋盲疾病的一种主要类型，Usher综合征。我们研究了MYO7A突变小鼠(Shaker1)视网膜中的突变表型，目的是阐明肌球蛋白Vila在视网膜中的作用(S)以及可能导致USH1B患者光感受器退化的原因。描述了一种光感受器缺陷。在这里，我们报告了在MYO7A基因缺失的小鼠中，视网膜色素上皮(RPE)对光感受器外节段盘的吞噬功能异常。无论是在体内还是在RPE细胞的原代培养中，在没有MYO7A的情况下，摄取的圆盘从顶端区域向外的运输都受到抑制。对培养的成熟细胞的结果是相同的，无论盘来自野生型还是突变小鼠，因此证明RPE是这种缺陷的来源。被抑制的转运似乎延迟了吞噬小体-溶酶体的融合，因为在突变的RPE中，吞噬盘的降解较慢。此外，体内摄入的盘膜较少，可能是因为吞噬小体从根尖突起的延迟去除阻碍了对额外盘膜的摄取。我们得出结论，MYO7A是RPE中摄取的盘膜的正常处理所必需的，主要是吞噬小体进入细胞体的基础运输，在那里它们与溶酶体融合。由于RPE对光感受器盘的吞噬作用已被证明是光感受器细胞存活的关键，这一缺陷可能导致USH1B的进行性失明。
Mutations in the myosin Vila gene (MYO7A) cause Usher syndrome type 1B (USH1B), a major type of the deaf-blind disorder, Usher syndrome. We have studied mutant phenotypes in the retinas of Myo7a mutant mice (shaker1), with the aim of elucidating the role(s) of myosin Vila in the retina and what might underlie photoreceptor degeneration in USH1B patients. A photoreceptor defect has been described. Here, we report that the phagocytosis of photoreceptor outer segment disks by the retinal pigment epithelium (RPE) is abnormal in Myo7a null mice. Both in vivo and in primary cultures of RPE cells, the transport of ingested disks out of the apical region is inhibited in the absence of Myo7a. The results with the cultured RIPE cells were the same, irrespective of whether the disks came from wild-type or mutant mice, thus demonstrating that the RPE is the source of this defect. The inhibited transport seems to delay phagosome-lysosomal fusion, as the degradation of ingested disks was slower in mutant RPE. Moreover, fewer packets of disk membranes were ingested in vivo, possibly because retarded removal of phagosomes from the apical processes inhibited the ingestion of additional disk membranes. We conclude that Myo7a is required for the normal processing of ingested disk membranes in the RPE, primarily in the basal transport of phagosomes into the cell body where they then fuse with lysosomes. Because the phagocytosis of photoreceptor disks by the RPE has been shown to be critical for photoreceptor cell viability, this defect likely contributes to the progressive blindness in USH1B.