Imprinted genes in mammals are expressed from only one of the parental chromosomes, and are crucial for placental development and fetal growth. The insulin-like growth factor II gene (Igf2) is paternally expressed in the fetus and placenta. Here we show that deletion from the Igf2 gene of a transcript (P0) specifically expressed in the labyrinthine trophoblast of the placenta leads to reduced growth of the placenta, followed several days later by fetal growth restriction. The fetal to placental weight ratio is thus increased in the absence of the P0 transcript. We show that passive permeability for nutrients of the mutant placenta is decreased, but that secondary active placental amino acid transport is initially upregulated, compensating for the decrease in passive permeability. Later the compensation fails and fetal growth restriction ensues. Our study provides experimental evidence for imprinted gene action in the placenta that directly controls the supply of maternal nutrients to the fetus, and supports the genetic conflict theory of imprinting. We propose that the Igf2 gene, and perhaps other imprinted genes, control both the placental supply of, and the genetic demand for, maternal nutrients to the mammalian fetus.

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Epidemiological evidence links an individual's susceptibility to chronic disease in adult life to events during their intrauterine phase of development. Biologically this should not be unexpected, for organ systems are at their most plastic when progenitor cells are proliferating and differentiating. Influences operating at this time can permanently affect their structure and functional capacity, and the activity of enzyme systems and endocrine axes. It is now appreciated that such effects lay the foundations for a diverse array of diseases that become manifest many years later, often in response to secondary environmental stressors. Fetal development is underpinned by the placenta, the organ that forms the interface between the fetus and its mother. All nutrients and oxygen reaching the fetus must pass through this organ. The placenta also has major endocrine functions, orchestrating maternal adaptations to pregnancy and mobilizing resources for fetal use. In addition, it acts as a selective barrier, creating a protective milieu by minimizing exposure of the fetus to maternal hormones, such as glucocorticoids, xenobiotics, pathogens, and parasites. The placenta shows a remarkable capacity to adapt to adverse environmental cues and lessen their impact on the fetus. However, if placental function is impaired, or its capacity to adapt is exceeded, then fetal development may be compromised. Here, we explore the complex relationships between the placental phenotype and developmental programming of chronic disease in the offspring. Ensuring optimal placentation offers a new approach to the prevention of disorders such as cardiovascular disease, diabetes, and obesity, which are reaching epidemic proportions.

The intrauterine conditions in which the mammalian fetus develops have an important role in regulating the function of its physiological systems later in life. Changes in the intrauterine availability of nutrients, oxygen, and hormones program tissue development and lead to abnormalities in adult cardiovascular and metabolic function in several species. The timing, duration, severity, and type of insult during development determines the specific physiological outcome. Intrauterine programming of physiological systems occurs at the gene, cell, tissue, organ, and system levels and causes permanent structural and functional changes, which can lead to overt disease, particularly with increasing age.

The placenta is arguably the most important organ of the body, but paradoxically the most poorly understood. During its transient existence, it performs actions that are later taken on by diverse separate organs, including the lungs, liver, gut, kidneys and endocrine glands. Its principal function is to supply the fetus, and in particular, the fetal brain, with oxygen and nutrients. The placenta is structurally adapted to achieve this, possessing a large surface area for exchange and a thin interhaemal membrane separating the maternal and fetal circulations. In addition, it adopts other strategies that are key to facilitating transfer, including remodelling of the maternal uterine arteries that supply the placenta to ensure optimal perfusion. Furthermore, placental hormones have profound effects on maternal metabolism, initially building up her energy reserves and then releasing these to support fetal growth in later pregnancy and lactation post-natally. Bipedalism has posed unique haemodynamic challenges to the placental circulation, as pressure applied to the vena cava by the pregnant uterus may compromise venous return to the heart. These challenges, along with the immune interactions involved in maternal arterial remodelling, may explain complications of pregnancy that are almost unique to the human, including pre-eclampsia. Such complications may represent a trade-off against the provision for a large fetal brain.

Epidemiological findings and experimental studies in animals have shown that individual tissues and whole organ systems can be programmed in utero during critical periods of development with adverse consequences for their function in later life. Detailed morphometric analyses of the data have shown that certain patterns of intrauterine growth, particularly growth retardation, can be related to specific postnatal outcomes. Since hormones regulate fetal growth and the development of individual fetal tissues, they have a central role in intrauterine programming. Hormones such as insulin, insulin-like growth factors, thyroxine and the glucocorticoids act as nutritional and maturational signals and adapt fetal development to prevailing intrauterine conditions, thereby maximizing the chances of survival both in utero and at birth. However, these adaptations may have long-term sequelae. Of the hormones known to control fetal development, it is the glucocorticoids that are most likely to cause tissue programming in utero. They are growth inhibitory and affect the development of all the tissues and organ systems most at risk of postnatal pathophysiology when fetal growth is impaired. Their concentrations in utero are also elevated by all the nutritional and other challenges known to have programming effects. Glucocorticoids act at cellular and molecular levels to alter cell function by changing the expression of receptors, enzymes, ion channels and transporters. They also alter various growth factors, cytoarchitectural proteins, binding proteins and components of the intracellular signalling pathways. Glucocorticoids act, directly, on genes and, indirectly, through changes in the bioavailability of other hormones. These glucocorticoid-induced endocrine changes may be transient or persist into postnatal life with consequences for tissue growth and development both before and after birth. In the long term, prenatal glucocorticoid exposure can permanently reset endocrine systems, such as the somatotrophic and hypothalamic-pituitary -adrenal axes, which, in turn, may contribute to the pathogenesis of adult disease. Endocrine changes may, therefore, be both the cause and the consequence of intrauterine programming.

The mammalian fetus is unique in its dependence during gestation on the supply of maternal nutrients through the placenta. Maternal supply and fetal demand for nutrients need to be fine tuned for healthy growth and development of the fetus along its genetic trajectory. An altered balance between supply and demand can lead to deviations from this trajectory with long-term consequences for health. We have previously shown that in a knockout lacking the imprinted placental-specific Igf2 transcript (P0), growth of the placenta is compromised from early gestation but fetal growth is normal until late gestation, suggesting functional adaptation of the placenta to meet the fetal demands. Here, we show that placental transport of glucose and amino acids are increased in the Igf2 P0 ؉/؊ null and that this up-regulation of transport occurs, at least in part, through increased expression of the transporter genes Slc2a3 and Slc38a4, the imprinted member of the System A amino acid transporter gene family. Decreasing fetal demand genetically by removal of fetal Igf2 abolished up-regulation of both transport systems and reduced placental System A amino acid transport activity and expression of Slc38a2 in late gestation. Our results provide direct evidence that the placenta can respond to fetal demand signals through regulation of expression of specific placental transport systems. Thus, crosstalk between an imprinted growth demand gene (Igf2) and placental supply transporter genes (Slc38a4, Slc38a2, and Slc2a3) may be a component of the genetic control of nutrient supply and demand during mammalian development.genomic imprinting ͉ nutrient transporters

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