Regulation of Supply and Demand for Maternal Nutrients in Mammals by Imprinted Genes (PDF - 1.86 MB)
Drs. Miguel Constância1, Abigail Fowden2, Anne Ferguson-Smith3, Wendy Dean1, Colin Sibley4 and Wolf Reik1
1Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge United Kingdom; 2The Physiological Laboratory, University of Cambridge; 3Department of Anatomy, University of Cambridge, United Kingdom; 4Academic Unit of Child Health, University of Manchester, United Kingdom
Imprinted genes are a class of genes found in placental mammals, marsupials, and seed plants whose expression depends on their parental origin. In mammals, a substantial proportion of imprinted genes are involved in the control of fetal growth. In general, paternally expressed imprinted genes enhance fetal growth, whereas maternally expressed ones suppress it (Tycko & Morison, 2002). Imprinted genes may modulate fetal growth in distinct ways: they may regulate the growth rate of fetal tissues, thereby controlling nutrient demand by the fetus, or they may regulate the growth and transport capacity of the placenta, therefore controlling the supply of nutrients. These functions are difficult to discern experimentally because most imprinted genes are expressed in fetal tissues as well as in the placenta, where they may play additional roles. We are using knockout mouse models to genetically separate the role of imprinted genes in the placenta from its fetal action and performing in vivo physiology assays in these models to study placental transport capacity. Our recent studies on Igf2 (insulin-like growth factor 2) provide experimental support for the hypothesis that imprinted genes have central roles in controlling both the fetal demand for, and the placental supply of, maternal nutrients (Reik et al, 2003). By knocking out a placental-specific Igf2 transcript (P0) we have generated a mouse model for IUGR that mimics IUGR in humans. In this model we specifically manipulated the growth and transport capacity of the placenta and hence the supply of nutrients to the fetus, but not fetal demand (Constância et at, 2002). Intriguingly, the fetal growth restriction was only apparent in late gestation, although the reduction in supply of nutrients was noted much earlier. We found that the P0 deficient placenta upregulates active transport of amino acids (system A), and we hypothesize that this is in order to meet the levels of demand for nutrients by the "under-nourished" growing fetus. At the molecular level, a preliminary analysis shows that this increase in amino acid transport is accompanied by an increase in transcript levels of an imprinted amino acid transporter protein, Slc38a4. This work shows that interactions between demand (fetal) and supply (placenta) systems are important to fine tune mammalian growth and development. We suggest that the function of many imprinted genes are linked to perform these functions in mammalian species, and that positive effects on supply and demand (paternally expressed genes) are balanced by negative effects on supply (maternally expressed genes). These data and hypotheses are important, as deregulation of supply and demand affects fetal growth and has long-term consequences for health in mammals.
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Reik W, Constancia M, Fowden A, Anderson N, Dean W, Ferguson-Smith A, Tycko B, Sibley C. Regulation of supply and demand for maternal nutrients in mammals by imprinted genes. J Physiol 2003, 547(Pt 1): 35-44.
Constancia M, Hemberger M, Hughes J, Dean W, Ferguson-Smith A, Fundele R, Stewart F, Kelsey G, Fowden A, Sibley C, Reik W. Placental-specific IGF-II is a major modulator for placental and fetal growth. Nature 2002, 417:945-8.