034. Nutrient sensing by the early mouse embryo: hexosamine biosynthesis and glucose signalling during preimplantation development
M. Pantaleon A and P. L. Kaye ASchool of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia
Reproduction, Fertility and Development 17(9) 70-70 https://doi.org/10.1071/SRB05Abs034
Submitted: 26 July 2005 Accepted: 26 July 2005 Published: 5 September 2005
Abstract
Adequate nutrient supply prior to implantation is not only essential to early embryonic growth and development but has also been implicated in metabolic programming events that influence later stage development and the onset of adult disease. The molecular mechanisms involved in early embryonic nutrient sensing and subsequent programming however have not yet been determined.
Glucose can act as an essential molecular signal for metabolic differentiation and blastocyst formation.1,2 Our work demonstrates that propagation of this nutrient signal involves glucose metabolism through the hexosamine biosynthetic pathway, whose end-product, uridine 5′-diphospho-N-acetylglucosamine (UDP-Glc-NAc) acts as a donor substrate adding a single O-linked β-N-acetylglucosamine (O-GlcNAc) unit to serine and threonine residues of nucleocytoplasmic proteins. The number of proteins modified by this O-linked glycosylation is large and includes transcription factors, cytoskeletal components, metabolic enzymes and other cellular signaling components. This tightly regulated and dynamic modification operates in a functionally reciprocal relationship to the more familiar phosphorylation at the same sites hence altering the activity and/or stability of targeted proteins and providing a mechanism for modulating cellular physiology in response to nutrient availability.
We show that early embryonic glucose exposure, whilst not essential for energy generation during cleavage development, is nonetheless critical for the maintenance of cellular homeostasis with perturbations in glucose levels during early development leading to decreased levels of cell survival. Furthermore, using antisera specific for O-GlcNAc we have examined levels of O-glycosylated proteins in early mouse embryos in response to the presence or absence of glucose and find dramatically reduced global levels of O-linked glycosylation as well as altered nuclear levels of key transcription factors in embryos deprived of glucose.
We believe that this is the first demonstration of a nutrient effect on levels of transcriptional regulators in early development. Elucidation of the mechanisms by which the nutrient environment influences embryonic development is of fundamental importance to our understanding of the origins of adult disease.
(1) Pantaleon et al. (2001). Proc 32nd Annual SRB conference, Gold Coast, Qld. Abstract #42.
(2) Martin and Leese (1995). Mol. Reprod. Dev. 40, 436–443.
