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Genetic gradual reduction of OGT activity unveils the essential role of O-GlcNAc in the mouse embryo

The reversible glycosylation of nuclear and cytoplasmic proteins (O-GlcNAcylation) is catalyzed by a single enzyme, namely O-GlcNAc transferase (OGT). The mammalian Ogt gene is X-linked, and it is essential for embryonic development and for the viability of proliferating cells. We perturbed OGT’s fu...

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Main Authors: Formichetti, Sara (Author) , Sadowska, Agnieszka (Author) , Ascolani, Michela (Author) , Hansen, Julia (Author) , Wahrheit-Ganter, Kerstin (Author) , Lancrin, Christophe (Author) , Humphreys, Neil (Author) , Boulard, Mathieu (Author)
Format: Article (Journal)
Language:English
Published: January 9, 2025
In: PLoS Genetics
Year: 2025, Volume: 21, Issue: 1, Pages: 1-37
ISSN:1553-7404
DOI:10.1371/journal.pgen.1011507
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1371/journal.pgen.1011507
Verlag, lizenzpflichtig, Volltext: https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1011507
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Author Notes:Sara Formichetti, Agnieszka Sadowska, Michela Ascolani, Julia Hansen, Kerstin Ganter, Christophe Lancrin, Neil Humphreys, Mathieu Boulard
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Summary:The reversible glycosylation of nuclear and cytoplasmic proteins (O-GlcNAcylation) is catalyzed by a single enzyme, namely O-GlcNAc transferase (OGT). The mammalian Ogt gene is X-linked, and it is essential for embryonic development and for the viability of proliferating cells. We perturbed OGT’s function in vivo by creating a murine allelic series of four single amino acid substitutions, reducing OGT’s catalytic activity to a range of degrees. The severity of the embryonic lethality was proportional to the extent of impairment of OGT’s catalysis, demonstrating that the O-GlcNAc modification itself is required for early development. We identified hypomorphic Ogt alleles that perturb O-GlcNAc homeostasis while being compatible with embryogenesis. The analysis of the transcriptomes of the mutant embryos at different developmental stages suggested a sexually-dimorphic developmental delay caused by the decrease in O-GlcNAc. Furthermore, a mild reduction of OGT’s enzymatic activity was sufficient to loosen the silencing of endogenous retroviruses in vivo.
Item Description:Gesehen am 06.08.2025
Physical Description:Online Resource
ISSN:1553-7404
DOI:10.1371/journal.pgen.1011507

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