The role of hexosamine biosynthesis and signaling in early development

Although the culture requirements and the metabolic profile of the preimplantation embryo have been thoroughly investigated since their first successful culture in a defined medium, now more than 50 years ago (Whitten, Nature 177:96, 1956), it is only recently that we have begun to appreciate the impact of the environment on life-course trajectory. The mechanisms involved in how nutrient availability may potentially modulate developmental potential are consequently not well defined. Originally thought of as simple energy substrates and biosynthetic precursors, the currently emerging paradigm suggests that nutrients may act in non-classical roles to impact on developmental potential. This is now an area of considerable activity thanks to pioneering epidemiological studies (Barker et al., BMJ 298:564-7, 1989) that have led to the establishment of the Developmental Origins of Health and Disease (DoHAD) hypothesis and a whole new field of research activity. The period prior to implantation is of particular interest as this has been identified as a critical window of developmental sensitivity to environmental or nutrient stress (Fleming et al., Biol Reprod 71:1046-54, 2004a). This review seeks specifically to explore the pivotal role of glucose in early mouse development and the mechanisms by which it may impact on the cellular functions of the developing embryo. The emerging paradigm suggests that this humble hexose sugar may be at the heart of a rather sophisticated mechanism of cellular control that not only impacts on cellular proliferation and viability in the short term but on cellular memory through to the next generation.