Miguel Constância
(Miguel Constância has moved to the Institute of Metabolic Science
within the University of Cambridge) and can be contacted there.


• Recent, selected Publications
• Group Members

Imprinting, nutrient supply and fetal growth

The mammalian fetus acquires maternal nutrients through the placenta. The placenta comprises two components: a fetal portion that develops from trophoblast derivatives (the first lineage specified in the early embryo) and a maternal portion derived from the inner layer of the uterine wall (endometrium). The fetal circulation lies sufficiently close to the mother's circulation so that efficient transfer can occur between them through the exchange barrier made up by the fetus.

The ability of the fetus to directly exploit maternal resources, thereby influencing its own development and growth, forms the basis of the theory of evolution of imprinting known as kinship or genetic conflict. Parental genomes are asymmetric in their interests: paternally inherited genes have the “desire” to make large, fit babies, while the “desire” of maternally inherited genes is to withhold resources for future offspring. The prediction that imprinted genes have substantial control over size at birth has been confirmed by a number of studies, with many paternally expressed genes promoting growth and maternally expressed genes suppressing growth.

The different interests of parental genomes are played out in the fetus, at the level of demand for resources, and in the placenta, at the level of supply of resources. We found evidence that imprinting is important in regulating the amount of nutrients which is received by the mammalian fetus through the placenta. We eliminated the paternally expressed Igf2 from the placenta and measured the flow of nutrients from the mother to the fetus. It was observed that nutrient exchange was reduced, thus leading to fetal growth restriction. We also found that Igf2 expressed in fetal tissues, which is secreted into the blood stream, signals increased demand to the placenta.


These findings led us to suggest that imprinted genes have central roles in the genetic control of both fetal demand for, and placental supply of, maternal nutrients. We recently found that an important mechanism by which placentas respond to fetal nutrient demand is by increasing the amounts of the imprinted amino-acid nutrient transporter Slc38a4. Using various placenta-specific or fetus-specific knockouts of imprinted growth controllers, we now aim to define the precise roles these genes have in the regulation of supply and demand for nutrients during mammalian development in utero.

The genetic engineering of these mouse mutants is aimed at manipulating growth such that:
(a) the placenta but not the fetus is growth restricted or overgrown
(b) the fetus but not placenta is growth restricted or overgrown
(c) both placenta and fetus are growth restricted or overgrown


In these models, we systematically determine effects on placental structure using morphometric techniques, effects on placental transport capacity by measuring materno-fetal transfer of radioactively labeled solutes and examine the signaling from the fetus to the placenta by measuring expression of key transporter proteins (systems of transport of amino acids; glucose transporters). We are also making use of genome-wide transcriptional profiling approaches to identify additional key nutrient demand and supply signaling molecules.

These experiments will allow us to understand how the fetus “communicates” to the placenta to control nutrient supply and hence growth, and apply these insights to human intra-uterine growth disorders. Knowledge of how nutrient supply and demand is genetically regulated is crucial for understanding the mechanisms of fetal growth restriction. Intrauterine growth restriction affects up to 10% of all human pregnancies, and is associated with increased risk of morbidity and mortality in the neonatal period. Even within the normal range, smaller size at birth is associated with an increased incidence of cardiovascular and metabolic diseases in later life.

Imprinting, growth programming and disease in later life

Changes in imprinting might explain why restricted growth of the fetus in the womb can be associated with an increased risk of cardiovascular disease, diabetes and mental defects later in life (the ‘fetal programming’ hypothesis of adult diseases). We are interested in testing the hypothesis that changes in expression in imprinted genes provides a genetic link between the provision of nutrients, the intrauterine growth rate, and consequently the programming of fetal systems determining the risk of disease in adulthood. In particular, we are interested to know how environmental influences during life in the womb (e.g. nutrition) might affect epigenetic marks and imprinting, thereby shifting resource regulation over the course of a lifetime.


Recent, selected publications

Ozanne SE, Constancia M (2007) Mechanisms of disease: the developmental origins of disease and the role of the epigenotype.
Nature Clinical Practice Endocrinology and Metabolism 3 539-546
http://dx.doi.org/10.1038/ncpendmet0531

Monk D, Sanches R, Arnaud P, Apostolidou S, Hills FA, Abu-Amero S, Murrell AM, Friess H, Reik W, Stanier P, Constancia M, Moore GE (2006) Imprinting of IGF2 P0 transcript and novel alternatively spliced INS-IGF2 isoforms show differences between mouse and human.
Human Molecular Genetics 15 1259-1269
http://dx.doi.org/10.1093/hmg/dd1041

Constancia M, Angiolini E, Sandovici I, Smith P, Smith R, Kelsey GD, Dean WL, Ferguson-Smith AC, Sibley CP, Reik W, Fowden A (2005) Adaptation of nutrient supply to fetal demand in the mouse involves interaction between the Igf2 gene and placental transporter systems.
Proceedings of the National Academy of Sciences of the United States of America 102 19219-19224
http://dx.doi.org/10.1073/pnas.0504468103

Sibley CP, Coan PM, Ferguson-Smith AC, Dean WL, Hughes J, Smith P, Reik W, Burton GJ, Fowden AL, Constancia M (2004) Placental-specific insulin-like growth factor 2 (Igf2) regulates the diffusional exchange characteristics of the mouse placenta.
Proceedings of the National Academy of Sciences of the United States of America 101 8204-8208
http://dx.doi.org/10.1073/pnas.0402508101

Group Members

Ionel Sandovici - Postdoc

Gerrard Peck - Research Assistant

Emily Angiolini - PhD Student

Katharina Hoelle - PhD Student

Noel Smith - Visitor