Cambridge scientists have identified a key signal that the fetus uses to
control its supply of nutrients from the placenta, revealing a tug-of-war
between genes inherited from the father and from the mother. The study,
carried out in mice, could help explain why some babies grow poorly in the
womb.
As the fetus grows, it needs to communicate its increasing needs for food to
the mother. It receives its nourishment via blood vessels in the placenta, a
specialised organ that contains cells from both baby and mother.
Between 10% and 15% of babies grow poorly in the womb, often showing reduced
growth of blood vessels in the placenta. In humans, these blood vessels
expand dramatically between mid and late gestation, reaching a total length
of approximately 320 kilometres at term.
In a study published today in Developmental Cell, a team led by scientists
at the University of Cambridge used genetically engineered mice to show how
the fetus produces a signal to encourage growth of blood vessels within the
placenta. This signal also causes modifications to other cells of the
placenta to allow for more nutrients from the mother to go through to the
fetus.
Dr Ionel Sandovici, the paper’s first author, said: “As it grows in the
womb, the fetus needs food from its mum, and healthy blood vessels in the
placenta are essential to help it get the correct amount of nutrients it
needs.
“We’ve identified one way that the fetus uses to communicate with the
placenta to prompt the correct expansion of these blood vessels. When this
communication breaks down, the blood vessels don’t develop properly and the
baby will struggle to get all the food it needs.”
The team found that the fetus sends a signal known as IGF2 that reaches the
placenta through the umbilical cord. In humans, levels of IGF2 in the
umbilical cord progressively increase between 29 weeks of gestation and
term: too much IGF2 is associated with too much growth, while not enough
IGF2 is associated with too little growth. Babies that are too large or too
small are more likely to suffer or even die at birth, and have a higher risk
to develop diabetes and heart problems as adults.
Dr Sandovici added: “We’ve known for some time that IGF2 promotes the growth
of the organs where it is produced. In this study, we’ve shown that IGF2
also acts like a classical hormone – it’s produced by the fetus, goes into
the fetal blood, through the umbilical cord and to the placenta, where it
acts.”
Particularly interesting is what their findings reveal about the tussle
taking place in the womb.
In mice, the response to IGF2 in the blood vessels of the placenta is
mediated by another protein, called IGF2R. The two genes that produce IGF2
and IGF2R are ‘imprinted’ – a process by which molecular switches on the
genes identify their parental origin and can turn the genes on or off. In
this case, only the copy of the igf2 gene inherited from the father is
active, while only the copy of igf2r inherited from the mother is active.
Lead author Dr Miguel Constância, said: “One theory about imprinted genes is
that paternally-expressed genes are greedy and selfish. They want to extract
the most resources as possible from the mother. But maternally-expressed
genes act as countermeasures to balance these demands.”
“In our study, the father’s gene drives the fetus’s demands for larger blood
vessels and more nutrients, while the mother’s gene in the placenta tries to
control how much nourishment she provides. There’s a tug-of-war taking
place, a battle of the sexes at the level of the genome.”
The team say their findings will allow a better understanding of how the
fetus, placenta and mother communicate with each other during pregnancy.
This in turn could lead to ways of measuring levels of IGF2 in the fetus and
finding ways to use medication to normalise these levels or promote normal
development of placental vasculature.
The researchers used mice, as it is possible to manipulate their genes to
mimic different developmental conditions. This enables them to study in
detail the different mechanisms taking place. The physiology and biology of
mice have many similarities with those of humans, allowing researchers to
model human pregnancy, in order to understand it better.
The lead researchers are based at the Department of Obstetrics and
Gynaecology, the Medical Research Council Metabolic Diseases Unit, part of
the Wellcome-MRC Institute of Metabolic Science, and the Centre for
Trophoblast Research, all at the University of Cambridge.
The research was largely funded by the Biotechnology and Biological Sciences
Research Council, Medical Research Council, Wellcome Trust and Centre for
Trophoblast Research.
Reference:
Sandovici, I et al. The Imprinted Igf2-Igf2r Axis is Critical for Matching
Placental Microvasculature Expansion to Fetal Growth. Developmental Cell; 10
Jan 2022:
DOI: 10.1016/j.devcel.2021.12.005
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