Department of Ophthalmology & Vision Science, University of California Davis, Davis, California, United States.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States.
Invest Ophthalmol Vis Sci. 2023 Jan 3;64(1):18. doi: 10.1167/iovs.64.1.18.
Foveoschisis involves the pathologic splitting of retinal layers at the fovea, which may occur congenitally in X-linked retinoschisis (XLRS) or as an acquired complication of myopia. XLRS is attributed to functional loss of the retinal adhesion protein retinoschisin 1 (RS1), but the pathophysiology of myopic foveoschisis is unclear due to the lack of animal models. Here, we characterized a novel nonhuman primate model of myopic foveoschisis through clinical examination and multimodal imaging followed by morphologic, cellular, and transcriptional profiling of retinal tissues and genetic analysis.
We identified a rhesus macaque with behavioral and anatomic features of myopic foveoschisis, and monitored disease progression over 14 months by fundus photography, fluorescein angiography, and optical coherence tomography (OCT). After necropsy, we evaluated anatomic and cellular changes by immunohistochemistry and transcriptomic changes using single-nuclei RNA-sequencing (snRNA-seq). Finally, we performed Sanger and whole exome sequencing with focus on the RS1 gene.
Affected eyes demonstrated posterior hyaloid traction and progressive splitting of the outer plexiform layer on OCT. Immunohistochemistry showed increased GFAP expression in Müller glia and loss of ramified Iba-1+ microglia, suggesting macro- and microglial activation with minimal photoreceptor alterations. SnRNA-seq revealed gene expression changes predominantly in cones and retinal ganglion cells involving chromatin modification, suggestive of cellular stress at the fovea. No defects in the RS1 gene or its expression were detected.
This nonhuman primate model of foveoschisis reveals insights into how acquired myopic traction leads to phenotypically similar morphologic and cellular changes as congenital XLRS without alterations in RS1.
黄斑劈裂涉及黄斑区视网膜层的病理性分裂，这种情况可能在 X 连锁性视网膜劈裂症（XLRS）中先天发生，也可能是近视的后天并发症。XLRS 归因于视网膜粘连蛋白 1（RS1）的功能丧失，但由于缺乏动物模型，近视性黄斑劈裂的病理生理学尚不清楚。在这里，我们通过临床检查和多模态成像，对新型非人类灵长类动物的近视性黄斑劈裂模型进行了特征描述，然后对视网膜组织进行形态学、细胞学和转录组学分析，并进行了基因分析。
我们鉴定了一只具有近视性黄斑劈裂行为和解剖特征的恒河猴，并通过眼底照相、荧光素血管造影和光学相干断层扫描（OCT）监测疾病在 14 个月内的进展。尸检后，我们通过免疫组织化学评估解剖和细胞变化，并通过单细胞 RNA 测序（snRNA-seq）评估转录组变化。最后，我们对 RS1 基因进行了 Sanger 和全外显子测序。
受影响的眼睛在 OCT 上显示后玻璃体牵引和外丛状层的进行性分裂。免疫组织化学显示 Müller 胶质细胞中 GFAP 表达增加，有分支的 Iba-1+小胶质细胞丢失，提示巨细胞和小胶质细胞激活，光感受器改变最小。snRNA-seq 显示主要在视锥细胞和视网膜神经节细胞中发生基因表达变化，涉及染色质修饰，提示黄斑区细胞应激。未发现 RS1 基因或其表达缺陷。
这种非人类灵长类动物的黄斑劈裂模型揭示了获得性近视牵引如何导致与先天性 XLRS 相似的形态和细胞变化，而不会改变 RS1。
