O-linked glycosylation and embryonic glucose sensitivity in the mouse

Pantaleon, Marie, Kafer, Georgia and Kaye, Peter (2007). O-linked glycosylation and embryonic glucose sensitivity in the mouse. In: Biology of Reproduction: Meeting Abstracts. 40th Annual Meeting of the Society for the Study of Reproduction (SSR 2007), San Antonio, Texas, United States, (165-165). 21–25 July 2007.

Author Pantaleon, Marie
Kafer, Georgia
Kaye, Peter
Title of paper O-linked glycosylation and embryonic glucose sensitivity in the mouse
Conference name 40th Annual Meeting of the Society for the Study of Reproduction (SSR 2007)
Conference location San Antonio, Texas, United States
Conference dates 21–25 July 2007
Proceedings title Biology of Reproduction: Meeting Abstracts   Check publisher's open access policy
Journal name Biology of Reproduction   Check publisher's open access policy
Place of Publication Madison, WI
Publisher Society of the Study of Reporduction
Publication Year 2007
Sub-type Poster
ISSN 0006-3363
Volume 77
Issue Suppl. 1
Start page 165
End page 165
Total pages 1
Language eng
Abstract/Summary Glucose is an essential signal for metabolic differentiationand blastocyst formation. In its absence compaction is disruptedand blastocyst formation attenuated dramatically. Propagationof this nutrient signal requires glucose flux through the hexosaminebiosynthetic pathway (HBP) whose main end product is the aminosugarnucleotide uridine 5'-diphospho-N-acetylglucosamine (UDP-GlcNAc).UDP-GlcNAc acts as a donor substrate for multiple glycosylationreactions including Olinked glycosylation, which involves theaddition of a single O-linked b-Nacetylglucosamine (O-GlcNAc)unit to serine and threonine residues of nucleocytoplasmic proteins.Currently, only two enzymes are known that regulate this modification.Addition of O-GlcNAc to target proteins is catalysed by b-linked-O-GlcNActransferase (OGT), whilst removal is mediated by an O-GlcNAc-selectiveb-N-acetylglucosaminidase (O-GlcNAcase). Many proteins are modifiedby O-linked glycosylation including transcription factors, cytoskeletalcomponents, metabolic enzymes and other cellular signaling componentsand machinery. This is a dynamic regulatory modification withfunctionally reciprocal relationship to phosphorylation at thesame sites hence altering the activity and/or stability of targetedproteins and providing a mechanism for modulating cellular physiologyin response to nutrient availability. We aimed to explore therole of O-GlcNAcylation in early development using inhibitionstudies. We also assessed the impact of altered flux thoughthe HBP on early development and O-GlcNAcylation. Mouse zygotes(18h post hCG) were cultured in simple KSOM medium with eitherOGT or O-GlcNAcase inhibitors (BADGP and streptozotocin respectively).Embryos were additionally cultured under conditions of hypoglycemia,hyperglycemia or supplementation with 0.2, 5, or 27mM glucosamine.Levels of Oglycosylation were examined by confocal immunofluorescenceand western immunoblotting using specific antisera that recognisethe b-OGlcNAc linkage. Nutrient and pharmacological treatmentsthat perturb levels of intracellular O-GlcNAc in the early embryoare detrimental to development. Moreover, whilst some flux throughHSP is required to activate the embryonic differentiative potential,excess flux is detrimental to embryo viability and blastocystformation indicating a tight level of cellular control for thispost-translational modification. As well as inhibition of blastocystformation increased O-glycosylation leads to a significant reductionin cell number with glucosamine (5mM) being more potent (53%reduction P<0.01 relative to control) than hyperglycemia(27mM glucose, 28% decrease relative to control). Interestinglywe find that O-glycosylation is increased in response to bothhypoglycemia and hyperglycaemia suggesting that O-GlcNAc maybe a sensor of embryonic nutrient stress. We propose that increasedO-glycosylation in response to nutrient stress compromises embryodevelopment by direct effects on multiple cellular proteinsincluding transcription factors. We conclude that glucose fluxthrough HBP and subsequent O-GlcNAcylation may be a key mechanismby which the early embryo senses and responds to perturbationsin its glucose environment.
Subjects 11 Medical and Health Sciences
Keyword Reproductive Biology
Q-Index Code CX
Q-Index Status Provisional Code
Institutional Status UQ
Additional Notes Special Issue - Section: "Fertilization and Early Embryogenesis" - Poster Abstract 355.

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Created: Mon, 18 Feb 2008, 14:21:57 EST