Role of nutrient-driven O-GlcNAc-posttranslational modification in pancreatic exocrine and endocrine islet development

Abstract

While the developing pancreas is exquisitely sensitive to nutrient supply in utero, it is not entirely clear how nutrient-driven post-translational modification of proteins impacts the pancreas during development. We hypothesized the nutrient-sensing enzyme O-GlcNAc transferase (Ogt) that catalyzes an O-GlcNAc-modification onto key target proteins integrates nutrient-signaling networks to regulate cell survival and development. We aimed to study the heretofore unknown role of Ogt in exocrine and endocrine islet development. By genetic manipulation in vivo and by using morphometric and molecular analyses such as immunofluorescence imaging and single cell RNA sequencing, we show the first evidence that Ogt regulates pancreas development. Genetic deletion of Ogt in pancreatic epithelium (OgtKOPanc) causes pancreas hypoplasia, in part by increased apoptosis and reduction of Pdx1 protein. Transcriptomic analysis of single-cell and bulk RNA-sequencing uncovered cell type heterogeneity and predicted upstream regulator proteins that mediate cell survival, including Pdx1, Ptf1a, p53, putative Ogt targets. In conclusion, these findings underscore the requirement of O-GlcNAcylation during pancreas development and show that Ogt is essential for pancreatic progenitor survival, providing a novel mechanistic link between nutrients and pancreas development.