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Abstract：
Thyroid hormone (TH) plays an essential role in cell proliferation, differentiation, and metabolism. Experimental and clinical studies have shown a potential association between TH signaling and retinal degeneration. The suppression of TH signaling protects cone photoreceptors in mouse models of retinal degeneration, whereas excessive TH signaling induces cone degeneration, manifested as reduced light response and a loss of cones. This work investigates the genes/transcriptomic alterations that might be involved in TH-induced cone degeneration in mice using single-cell RNA sequencing (scRNAseq) analysis. One-month-old C57BL/6 mice received triiodothyronine (T3, 20 µg/mL in drinking water) for 4 weeks as a model of hyperthyroidism/excessive TH signaling. At the end of the experiments, retinal cells were dissociated, and cell viability was analyzed before being subjected to scRNAseq. The resulting data were analyzed using the Seurat package and visualized using the Loupe browser. Among 155,866 single cells, we identified 14 cell clusters, representing various retinal cell types, with rod and cone clusters comprising 76% and 4.1% of the total cell population, respectively. Cone cluster transcriptomes demonstrated the most alterations after the T3 treatment, with 450 differentially expressed genes (DEGs), accounting for 38.5% of the total DEGs. Statistically significant changes in the expression of genes in the cone cluster revealed that phototransduction and oxidative phosphorylation were impaired after the T3 treatment, along with mitochondrial dysfunction. A pathway analysis also showed the activation of the sensory neuronal/photoreceptor stress pathways after the T3 treatment. Specifically, the eukaryotic initiation factor-2 signaling pathway and the cAMP response element-binding protein signaling pathway were upregulated. Thus, excessive TH signaling substantially affects cones at the transcriptomic level. The findings from this work provide an insight into how excessive TH signaling induces cone degeneration.
摘要：
甲状腺激素（TH）在细胞增殖中起着至关重要的作用，分化,和新陈代谢。实验和临床研究表明，TH信号与视网膜变性之间存在潜在的关联。抑制TH信号保护视网膜变性小鼠模型中的视锥细胞，而过度的TH信号诱导视锥细胞变性，表现为减少的光响应和锥体的损失。这项工作使用单细胞RNA测序（scRNAseq）分析研究了可能参与TH诱导的小鼠视锥变性的基因/转录组改变。一个月大的C57BL/6小鼠接受三碘甲状腺原氨酸（T3，饮用水中20µg/mL）4周作为甲状腺功能亢进/过度TH信号传导的模型。在实验结束时,视网膜细胞解离，并在进行scRNAseq之前分析细胞活力。使用Seurat软件包分析所得数据，并使用Loupe浏览器进行可视化。在155,866个单细胞中，我们确定了14个细胞簇，代表各种视网膜细胞类型，杆状和锥形簇占总细胞群的76%和4.1%，分别。在T3治疗后，锥形簇转录组表现出最大的变化，具有450个差异表达基因（DEGs），占总DEG的38.5%。视锥簇中基因表达的统计学显着变化表明，T3处理后，光转导和氧化磷酸化受损，以及线粒体功能障碍。途径分析还显示了T3处理后感觉神经元/光感受器应激途径的激活。具体来说,真核起始因子2信号通路和cAMP反应元件结合蛋白信号通路上调。因此，过度的TH信号在转录组水平上显著影响视锥细胞。这项工作的发现提供了对过度TH信号如何诱导视锥退化的见解。
