Overexpression of Pdx1, reduction of p53, or deletion of CHOP attenuates pancreas hypoplasia in mice with pancreas-specific O-GlcNAc transferase deletion

Alicia Wong, Samantha Pritchard, Mackenzie Moore, Brian Akhaphong, Nandini Avula, Megan Beetch, Yoshio Fujitani, Emilyn U. Alejandro

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Deletion of O-GlcNAc transferase (Ogt) in pancreatic epithelial progenitor cells results in pancreatic hypoplasia at birth, partly due to increased apoptosis during embryonic development. Constitutive loss of Ogt in β-cells results in increased ER stress and apoptosis, and in the Ogt-deficient pancreas, transcriptomic data previously revealed both tumor suppressor protein p53 and pancreatic duodenal homeobox 1 (Pdx1), key cell survival proteins in the developing pancreas, as upstream regulators of differentially expressed genes. However, the specific roles of these genes in pancreatic hypoplasia are unclear. In this study, we explored the independent roles of p53, ER stress protein CHOP, and Pdx1 in pancreas development and their use in the functional rescue of pancreatic hypoplasia in the context of Ogt loss. Using in vivo genetic manipulation and morphometric analysis, we show that Ogt plays a key regulatory role in pancreas development. Heterozygous, but not homozygous, loss of pancreatic p53 afforded a partial rescue of β-cell, α-cell, and exocrine cell masses, while whole body loss of CHOP afforded a partial rescue in pancreas weight and a full rescue in exocrine cell mass. However, neither was sufficient to fully mitigate pancreatic hypoplasia at birth in the Ogt-deficient pancreas. Furthermore, overexpression of Pdx1 in the pancreatic epithelium resulted in partial rescues in pancreas weight and β-cell mass in the Ogt loss background. These findings highlight the requirement of Ogt in pancreas development by targeting multiple proteins such as transcription factor Pdx1 and p53 in the developing pancreas.

Original languageEnglish (US)
Article number102878
JournalJournal of Biological Chemistry
Volume299
Issue number2
DOIs
StatePublished - Feb 2023

Bibliographical note

Funding Information:
The NIH funding was provided for E. U. A. (R01DK115720 and Regenerative Medicine Minnesota), University of Minnesota Foundation, McKnight Foundation, and the UMN Genomics Center. A. W. was supported by T32GM140936, S. P. and M. B. were supported by T32DK007203, and M. M. was supported by T32DK108733. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2023

Keywords

  • CHOP
  • ER stress
  • O-GlcNAc transferase
  • O-GlcNAcylation
  • Pdx1
  • beta-cell
  • islet
  • p53
  • pancreas development
  • transcription factors

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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