Grabinski Sarah E, Parsana Dhwani, Perkins Brian D
Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, United States.
Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, United States.
Front Mol Neurosci. 2023 May 24;16:1148840. doi: 10.3389/fnmol.2023.1148840. eCollection 2023.
Acute injury to the adult zebrafish retina triggers the release of pro-inflammatory cytokines and growth factors that stimulate multiple gene regulatory networks, which ultimately stimulate Müller glia to proliferate and regenerate neurons. In contrast, zebrafish carrying mutations in or undergo progressive loss of cone photoreceptors and exhibit signs of microglia activation and inflammation, but the mutants fail to stimulate a regeneration response. To identify transcriptional changes that occur in zebrafish mutants undergoing progressive photoreceptor degeneration, RNA-seq transcriptional profiling was performed on and retinas. The PANTHER Classification System was used to identify biological processes and signaling pathways that were differentially expressed between mutants and wild-type siblings during degeneration. As expected, genes associated with phototransduction were downregulated in and mutants compared to wild-type siblings. Although both and mutants undergo proliferation of rod precursors in response to retinal degeneration, the process of negatively regulating proliferation is enriched for upregulated genes, and this negative regulation may restrict proliferation of Müller glia and inhibit regeneration. A total of 815 differentially expressed genes (DEGs) were shared by and retinas. Genes in pathways associated with inflammation, apoptosis, stress response, and PDGF signaling were overrepresented. Identifying the genes and biological pathways that are common in zebrafish models of inherited retinal degeneration provides a foundation for future studies on the mechanisms that regulate cell death as well as processes that prohibit Müller cell reprogramming or proliferation in a model capable of retinal regeneration. The pathways will provide targets for future interventions that may promote successful regeneration of lost photoreceptors.
成年斑马鱼视网膜的急性损伤会触发促炎细胞因子和生长因子的释放，这些因子会刺激多个基因调控网络，最终刺激穆勒胶质细胞增殖并再生神经元。相比之下，携带 或 突变的斑马鱼会逐渐丧失视锥光感受器，并表现出小胶质细胞激活和炎症迹象，但这些突变体无法刺激再生反应。为了确定在经历渐进性光感受器退化的斑马鱼突变体中发生的转录变化，对 和 的视网膜进行了RNA测序转录谱分析。使用PANTHER分类系统来识别在退化过程中突变体和野生型同胞之间差异表达的生物学过程和信号通路。正如预期的那样，与光转导相关的基因在 和 突变体中与野生型同胞相比下调。尽管 和 的突变体都会因视网膜退化而使视杆前体细胞增殖，但负调控增殖的过程中上调基因富集，这种负调控可能会限制穆勒胶质细胞的增殖并抑制再生。 和 的视网膜共有815个差异表达基因（DEG）。与炎症、凋亡、应激反应和血小板衍生生长因子（PDGF）信号传导相关的通路中的基因过度表达。确定遗传性视网膜退化斑马鱼模型中常见的基因和生物学通路，为未来研究调节细胞死亡的机制以及在能够进行视网膜再生的模型中阻止穆勒细胞重编程或增殖的过程奠定了基础。这些通路将为未来可能促进丢失的光感受器成功再生的干预措施提供靶点。
