Nutrient regulation of growth factor signalling in human placenta

The in utero nutritional environment is crucial for both the prenatal and long-term health of the offspring. The placenta modifies its structure/function in response to maternal growth/nutritional signals to actively regulate maternal-to-fetus nutrient transfer and consequently optimise fetal development. Little is known about the molecular mechanisms involved in placental sensing of maternal nutrients. We postulate that nutrient flux through the hexosamine biosynthetic pathway (HBP), and downstream O-GlcNAcylation of proteins, influence placental growth and hormone secretion and in turn, modulate its capacity to supply nutrients to the fetus.Immunostaining of BeWo and first trimester placental tissue revealed expression of the enzymes responsible for O-GlcNAc addition (O-GlcNAc-transferase) and removal (O-GlcNAcase) and the presence of O-GlcNAc modified proteins. The effect of altering O-GlcNAcylation levels on placental function was investigated by treating BeWo cells (n=3) and first trimester explants (n=5) with a specific substrate of the HBP pathway, D-glucosamine (0.25mM, 1mM or 10mM) for 6, 24 or 48h. Treatment enhanced the level of O-GlcNAc-modified proteins dose- and time-dependently and also altered their cellular distribution with enhanced staining in nuclear speckles. Interestingly, the increase in O-GlcNAcylation was accompanied by a significant (p