Nuclear NAD+-biosynthetic enzyme NMNAT1 facilitates survival of developing retinal neurons

Despite mounting evidence that the mammalian retina is exceptionally reliant on proper NAD+ homeostasis for health and function, the specific roles of subcellular NAD+ pools in retinal development, maintenance, and disease remain obscure. Here, we show that deletion of the nuclear-localized NAD+ synthase nicotinamide mononucleotide adenylyltransferase-1 (NMNAT1) in the developing murine retina causes early and severe degeneration of photoreceptors and select inner retinal neurons via multiple distinct cell death pathways. This severe phenotype is associated with disruptions to retinal central carbon metabolism, purine nucleotide synthesis, and amino acid pathways. Furthermore, large-scale transcriptomics reveals dysregulation of a collection of photoreceptor and synapse-specific genes in NMNAT1 knockout retinas prior to detectable morphological or metabolic alterations. Collectively, our study reveals previously unrecognized complexity in NMNAT1-associated retinal degeneration and suggests a yet-undescribed role for NMNAT1 in gene regulation during photoreceptor terminal differentiation. mRNA profiles of Nmnat1-/- and wild-type control (Nmnat1 fl/fl) murine retinas at two ages: embryonic day 18.5 (E18.5) and postnatal day 4 (P4)尽管已有越来越多的研究证据表明，哺乳动物视网膜的健康与功能极度依赖于正常的烟酰胺腺嘌呤二核苷酸（NAD+）稳态，但亚细胞NAD+池在视网膜发育、维持及疾病进程中的具体作用仍有待阐明。本研究证实，在发育中的小鼠视网膜中敲除定位于细胞核的烟酰胺单核苷酸腺苷酰转移酶1（nicotinamide mononucleotide adenylyltransferase-1, NMNAT1），可通过多种不同的细胞死亡途径，引发感光细胞与特定内层视网膜神经元的早期严重变性。该严重表型与视网膜中心碳代谢、嘌呤核苷酸合成及氨基酸代谢通路的紊乱密切相关。此外，大规模转录组学分析显示，在可检测到形态学或代谢异常之前，NMNAT1敲除小鼠视网膜内的感光细胞及突触特异性基因集已出现表达失调。综上，本研究揭示了NMNAT1相关视网膜变性中此前未被认知的复杂机制，并提示NMNAT1在感光细胞终末分化过程中存在尚未被报道的基因调控功能。本数据集包含两个发育阶段（胚胎第18.5天[E18.5]与出生后第4天[P4]）的Nmnat1基因敲除（Nmnat1-/-）与野生型对照（Nmnat1 fl/fl）小鼠视网膜的mRNA转录谱。