Loss of O-GlcNAcase catalytic activity leads to defects in mouse embryogenesis

Villo Muha, Florence Authier, Zsombor Szoke-Kovacs, Sara Johnson, Jennifer Gallagher, Alison McNeilly, Rory McCrimmon, Lydia Teboul, Daan van Aalten (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

Abstract

O-GlcNAcylation is an essential posttranslational modification that has been implicated in neurodevelopmental and neurodegenerative disorders. O-GlcNAcase (OGA), the sole enzyme catalyzing the removal of O-GlcNAc from proteins, has emerged as a potential drug target. OGA consists of an N-terminal O-GlcNAcase catalytic domain and a C-terminal pseudo histone acetyl transferase (HAT) domain with unknown function. To investigate phenotypes specific to loss of O-GlcNAcase catalytic activity and dissect the role of the HAT domain, we generated a constitutive knock-in mouse line, carrying a mutation of a catalytic aspartic acid to alanine. These mice showed perinatal lethality and abnormal embryonic growth with skewed Mendelian ratios after day E18.5. We observed tissue specific changes in O-GlcNAc homeostasis regulation to compensate for loss of O-GlcNAcase activity. Using X-ray micro computed tomography on late gestation embryos, we identified defects in the kidney, brain, liver and stomach. Taken together, our data suggest that developmental defects during gestation may arise upon prolonged OGA inhibition specifically due to loss of O-GlcNAcase catalytic activity and independent of the function of the HAT domain.
Original languageEnglish
Article number100439
JournalJournal of Biological Chemistry
Early online date19 Feb 2021
DOIs
Publication statusE-pub ahead of print - 19 Feb 2021

Keywords

  • O-GlcNAcylation
  • O-GlcNAcase
  • perinatal lethality
  • mouse genetics
  • in vivo imaging
  • micro computed tomography
  • glycobiology
  • development
  • embryo

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