Nutrient-driven O-linked N-acetylglucosamine ( O-GlcNAc) Cycling Impacts Neurodevelopmental Timing and Metabolism

J Biol Chem. 2017 Apr 14;292(15):6076-6085. doi: 10.1074/jbc.M116.774042. Epub 2017 Feb 28.

Abstract

Nutrient-driven O-GlcNAcylation is strikingly abundant in the brain and has been linked to development and neurodegenerative disease. We selectively targeted the O-GlcNAcase (Oga) gene in the mouse brain to define the role of O-GlcNAc cycling in the central nervous system. Brain knockout animals exhibited dramatically increased brain O-GlcNAc levels and pleiotropic phenotypes, including early-onset obesity, growth defects, and metabolic dysregulation. Anatomical defects in the Oga knockout 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. In Oga KO mouse ES cells, we observed pronounced changes in expression of pluripotency markers, including Sox2, Nanog, and Otx2. These findings link the O-GlcNAc modification to mammalian neurogenesis and highlight the role of this nutrient-sensing pathway in developmental plasticity and metabolic homeostasis.

Keywords: O-GlcNAcylation; gene knockout; metabolism; neurodevelopment; stem cells.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Acetylglucosamine / genetics
  • Acetylglucosamine / metabolism*
  • Animals
  • Brain / cytology
  • Brain / metabolism*
  • Mice
  • Mice, Knockout
  • Mouse Embryonic Stem Cells / cytology
  • Mouse Embryonic Stem Cells / metabolism*
  • N-Acetylglucosaminyltransferases / genetics
  • N-Acetylglucosaminyltransferases / metabolism*
  • Nanog Homeobox Protein / genetics
  • Nanog Homeobox Protein / metabolism
  • Neurogenesis / physiology*
  • Organ Specificity / physiology
  • Otx Transcription Factors / genetics
  • Otx Transcription Factors / metabolism
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / metabolism

Substances

  • Nanog Homeobox Protein
  • Nanog protein, mouse
  • Otx Transcription Factors
  • Otx2 protein, mouse
  • SOXB1 Transcription Factors
  • Sox2 protein, mouse
  • N-Acetylglucosaminyltransferases
  • UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase
  • Acetylglucosamine