TY - JOUR
T1 - Role of nutrient-driven O-GlcNAc-post-translational modification in pancreatic exocrine and endocrine islet development
AU - Baumann, Daniel
AU - Wong, Alicia
AU - Akhaphong, Brian
AU - Jo, Seokwon
AU - Pritchard, Samantha
AU - Mohan, Ramkumar
AU - Chung, Grace
AU - Zhang, Ying
AU - Alejandro, Emilyn U.
N1 - Publisher Copyright:
© 2020 Company of Biologists Ltd. All rights reserved.
PY - 2020/4
Y1 - 2020/4
N2 - Although 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 that the nutrient-sensing enzyme O-GlcNAc transferase (Ogt), which catalyzes an O-GlcNAc-modification onto key target proteins, integrates nutrient-signaling networks to regulate cell survival and development. In this study, we investigated 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 the pancreatic epithelium (OgtKOPanc) causes pancreatic hypoplasia, in part by increased apoptosis and reduced levels of 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 and p53, which are 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.
AB - Although 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 that the nutrient-sensing enzyme O-GlcNAc transferase (Ogt), which catalyzes an O-GlcNAc-modification onto key target proteins, integrates nutrient-signaling networks to regulate cell survival and development. In this study, we investigated 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 the pancreatic epithelium (OgtKOPanc) causes pancreatic hypoplasia, in part by increased apoptosis and reduced levels of 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 and p53, which are 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.
KW - Hexosamine biosynthetic pathway
KW - Islet development
KW - Nutrients
KW - O-GlcNAc Transferase
KW - O-GlcNAcylation
KW - Pancreas development
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U2 - 10.1242/dev.186643
DO - 10.1242/dev.186643
M3 - Article
C2 - 32165492
AN - SCOPUS:85083622541
SN - 0950-1991
VL - 147
JO - Development (Cambridge)
JF - Development (Cambridge)
IS - 7
M1 - 186643
ER -