Center for Vascular and Developmental Biology, Feinberg Cardiovascular and Renal Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
Simpson Querrey Institute for BioNanotechnology, Northwestern University, 303 E. Superior Street, Chicago, IL, 60611, USA.
Nat Commun. 2023 Jul 14;14(1):4129. doi: 10.1038/s41467-023-39672-2.
Mammalian retinal metabolism favors aerobic glycolysis. However, the role of glycolytic metabolism in retinal morphogenesis remains unknown. We report that aerobic glycolysis is necessary for the early stages of retinal development. Taking advantage of an unbiased approach that combines the use of eye organoids and single-cell RNA sequencing, we identify specific glucose transporters and glycolytic genes in retinal progenitors. Next, we determine that the optic vesicle territory of mouse embryos displays elevated levels of glycolytic activity. At the functional level, we show that removal of Glucose transporter 1 and Lactate dehydrogenase A gene activity from developing retinal progenitors arrests eye morphogenesis. Surprisingly, we uncover that lactate-mediated upregulation of key eye-field transcription factors is controlled by the epigenetic modification of histone H3 acetylation through histone deacetylase activity. Our results identify an unexpected bioenergetic independent role of lactate as a signaling molecule necessary for mammalian eye morphogenesis.
哺乳动物视网膜代谢偏向有氧糖酵解。然而，糖酵解代谢在视网膜形态发生中的作用尚不清楚。我们报告称，有氧糖酵解对于视网膜发育的早期阶段是必需的。我们利用一种无偏见的方法，结合使用眼类器官和单细胞 RNA 测序，在视网膜祖细胞中鉴定出特定的葡萄糖转运蛋白和糖酵解基因。接下来，我们确定小鼠胚胎的视囊区域显示出升高的糖酵解活性。在功能水平上，我们表明从发育中的视网膜祖细胞中去除葡萄糖转运蛋白 1 和乳酸脱氢酶 A 基因活性会阻止眼睛形态发生。令人惊讶的是，我们发现，通过组蛋白去乙酰化酶活性，组蛋白 H3 乙酰化的表观遗传修饰控制着乳酸对关键眼区转录因子的上调。我们的结果确定了乳酸作为一种信号分子的意外的、独立于生物能量的作用，对于哺乳动物眼睛形态发生是必要的。
