Inosine monophosphate dehydrogenase (IMPDH) is a key regulatory enzyme in the de novo synthesis of the purine base guanine. Dominant mutations in human IMPDH1 cause photoreceptor degeneration for reasons that are unknown. Here, we sought to provide some foundational information on Impdh1a in the zebrafish retina. We found that in zebrafish, gene subfunctionalization due to ancestral duplication resulted in a predominant retinal variant expressed exclusively in rod and cone photoreceptors. This variant is structurally and functionally similar to the human IMPDH1 retinal variant and shares a reduced sensitivity to GTP-mediated inhibition. We also demonstrated that Impdh1a forms prominent protein filaments in vitro and in vivo in both rod and cone photoreceptor cell bodies, synapses, and to a lesser degree, in outer segments. These filaments changed length and cellular distribution throughout the day consistent with diurnal changes in both mRNA and protein levels. The loss of Impdh1a resulted in a substantial reduction of guanine levels, although cellular morphology and cGMP levels remained normal. Our findings demonstrate a significant role for IMPDH1 in photoreceptor guanine production and provide fundamental new information on the details of this protein in the zebrafish retina.

中文翻译：

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高度保守的斑马鱼 IMPDH 视网膜异构体产生大部分鸟嘌呤，并在感光细胞中形成动态蛋白丝。


肌苷单磷酸脱氢酶（IMPDH）是嘌呤碱基鸟嘌呤从头合成的关键调节酶。人类 IMPDH1 的显性突变会导致光感受器变性，原因尚不清楚。在这里，我们试图提供有关斑马鱼视网膜中 Impdh1a 的一些基础信息。我们发现，在斑马鱼中，由于祖先重复导致的基因亚功能化导致了主要在视杆细胞和视锥细胞光感受器中表达的主要视网膜变异。该变体在结构和功能上与人类 IMPDH1 视网膜变体相似，并且对 GTP 介导的抑制的敏感性降低。我们还证明，Impdh1a 在体外和体内的视杆细胞和视锥细胞感光细胞体、突触以及较小程度上在外部节段中形成突出的蛋白丝。这些细丝在一天中改变长度和细胞分布，与 mRNA 和蛋白质水平的昼夜变化一致。尽管细胞形态和 cGMP 水平保持正常，但 Impdh1a 的缺失导致鸟嘌呤水平大幅降低。我们的研究结果证明了 IMPDH1 在光感受器鸟嘌呤产生中的重要作用，并提供了有关斑马鱼视网膜中这种蛋白质细节的基本新信息。