It is widely known that a functional placenta is vital for normal embryonic development, but how much it may contribute to embryonic lethality has never before been systematically studied. Our research, published in Nature, demonstrates for the first time a remarkable co-association between embryonic lethality and placental defects.
A healthy placenta is vital to sustain normal pregnancy, ensuring proper supply of nutrients and oxygen to the baby. Abnormalities in the placenta can therefore have serious repercussions on fetal development, even causing miscarriage. Despite this, remarkably little is known about the identity of genes essential for a normal, functioning placenta and even less about the extent to which placental abnormalities contribute to defects that can arise as the fetus develops.
EXTENT AND IMPACT
We screened more than 100 mouse mutant lines in which affected embryos die before or immediately at birth. Almost 70% showed serious abnormalities in the placenta; in extreme cases this resulted in a placenta incapable of supporting embryo development beyond an early stage (Figure 1), in others, abnormalities in the developing embryo were accompanied by abnormalities in the placenta.
FIGURE 1 – mouse mid-gestation embryos and placentas shown at the same magnification
LEFT: a normal, wild-type (WT) genotype. RIGHT: Nubpl mutation (MUT) shows a growth-retarded and developmentally delayed embryo that will not survive until birth.
The placentas are stained for a marker of the exchange surface (MCT4, in green) across which nutrients are transported from the mother to the embryo. Note the complete absence of this cell type from the MUT placenta. Red staining is for a cell surface protein (CDH1) demarcating the cells underneath the MCT4-positive layer (arrows), which are greatly reduced in number in the MUT placenta.
EMBRYO AND PLACENTA DEFECTS ARE LINKED
Not only do these results identify a large number of genes essential for normal development of the placenta; in addition they show an intriguing link between placental defects and abnormalities affecting the brain , heart and vascular system of the embryo itself. The research, led by Dr Myriam Hemberger and her colleagues at the Babraham Institute demonstrates how common placental abnormalities are when embryos develop abnormally.
RESCUING EMBRYONIC LETHALITY
The team examined in detail three different genes that cause embryonic lethality, and showed that for two of them the loss of the gene affected proper differentiation of placental cell types. For one of these genes they were also able to show that embryo death was a direct result of gene loss in the placenta, by providing the mutant embryo with a genetically normal placenta, which prevented embryo death.
Although the DMDD study uses mice, the results are likely to be just as relevant for studying human pregnancy and the role the placenta may play in pregnancy complications and the origins of birth defects in newborn babies.
The Advance Online Publication on Nature, ‘Placentation defects are highly prevalent in embryonic lethal mouse mutants‘ is available now .
All image and phenotype data gathered by the DMDD programme is freely available to the scientific community at dmdd.org.uk. The research described in this blog post was funded by the Wellcome Trust with support from the Francis Crick Institute.