title: Nutrient-drivenO-linkedN-acetylglucosamine (O-GlcNAc) cycling impacts neurodevelopmental timing and metabolism.
abstract: Nutrient-drivenO-GlcNAcylation is strikingly abundant in the brain and has been linked to development and neurodegenerative disease. We selectively targeted theO-GlcNAcase (Oga) gene in the mouse brain to define the role ofO-GlcNAc cycling in the central nervous system. Brain knockout animals exhibited dramatically increased brainO-GlcNAc levels and pleiotropic phenotypes, including early-onset obesity, growth defects, and metabolic dysregulation. Anatomical defects in theOgaknockout included delayed brain differentiation and neurogenesis as well as abnormal proliferation accompanying a developmental delay. The molecular basis for these defects included transcriptional changes accompanying differentiating embryonic stem cells. InOgaKO mouse ES cells, we observed pronounced changes in expression of pluripotency markers, including Sox2, Nanog, and Otx2. These findings link theO-GlcNAc modification to mammalian neurogenesis and highlight the role of this nutrient-sensing pathway in developmental plasticity and metabolic homeostasis.
authors.affiliation: From the Laboratory of Cell and Molecular Biology, NIDDK, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Olivier-Van Stichelen
authors.affiliation: From the Laboratory of Cell and Molecular Biology, NIDDK, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.affiliation: From the Laboratory of Cell and Molecular Biology, NIDDK, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Marcy
authors.initials: M
authors.lastname: Comly
authors.affiliation: From the Laboratory of Cell and Molecular Biology, NIDDK, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Dona C
authors.initials: DC
authors.lastname: Love
authors.affiliation: From the Laboratory of Cell and Molecular Biology, NIDDK, National Institutes of Health, Bethesda, Maryland 20892 jah@helix.nih.gov.
authors.forename: John A
authors.identifier: 0000-0002-3154-9878
authors.initials: JA
authors.lastname: Hanover
mesh_terms: D000117:Acetylglucosamine / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism*; D000071317:Nanog Homeobox Protein / Q000235:genetics / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology*; D009928:Organ Specificity / Q000502:physiology; D051857:Otx Transcription Factors / Q000235:genetics / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D051857:Otx Transcription Factors; C497660:Otx2 protein, mouse; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D017351:N-Acetylglucosaminyltransferases; C063057:UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase; D000117:Acetylglucosamine
keywords: O-GlcNAcylation; gene knockout; metabolism; neurodevelopment; stem cells