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

5 Citations (Scopus)
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Abstract

O-GlcNAcylation is an essential post-translational 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 OGA catalytic domain and a C-terminal pseudo histone acetyltransferase (HAT) domain with unknown function. To investigate phenotypes specific to loss of OGA 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 OGA activity. Using X-ray microcomputed 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 because of loss of OGA catalytic activity and independent of the function of the HAT domain.

Original languageEnglish
Article number100439
Number of pages15
JournalJournal of Biological Chemistry
Volume296
Early online date19 Feb 2021
DOIs
Publication statusPublished - 2021

Keywords

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

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