Placenta defects a factor in prenatal deaths

The role of the placenta in healthy fetal development is being seriously under-appreciated according to a new paper published in Nature. The study was part of the Wellcome Trust-funded 'Deciphering the Mechanisms of Developmental Disorders (DMDD)' consortium.

Researchers at the Francis Crick Institute, in collaboration with the Babraham Institute, the Wellcome Sanger Institute, the University of Oxford and the Medical University of Vienna studied 103 genetic mutations in mice that cause embryos to die before birth. The results showed that the majority, almost 70%, cause defects in the placenta.

Each of the 103 gene mutations causes the loss of a particular factor. Many of these had not been previously linked to placenta development, hence the study highlights the unexpected number of genes that affect development of the placenta. By studying a select group of three genes in further detail, the team went on to show that the death of the embryo could be directly linked to defects in the placenta in one out of these three cases. This may mean that a significant number of genetic defects that lead to prenatal death may be due to abnormalities of the placenta, not just the embryo.

Although this research uses mice, the findings are likely to be highly relevant to complications during human pregnancy and the study highlights the need for more work to be done on investigating development of the placenta during human pregnancies.

The placenta is vital for normal pregnancy progression and embryo development in most animals that give birth to live young, including humans. It provides a unique and highly specialised interface between the embryo and the mother, ensuring an adequate provision of nutrients and oxygen to the embryo. The placenta is also involved in waste disposal from the embryo and produces important hormones that help sustain pregnancy and promote fetal growth.

Although previous research has highlighted the pivotal role of the placenta for a healthy pregnancy, its potential contribution to pregnancy complications and birth defects continues to be overlooked.

Scientists call mutations that cause death in the womb embryonic lethal. Mouse lethal genes are enriched for human disease genes and the affected embryos often show morphological abnormalities - changes to their shape and structure. Around one-third of all gene mutants studied in mouse are lethal or subviable, meaning that mutant offspring are less likely to survive than non-mutant pups.

The DMDD consortium investigates the detailed morphological abnormalities in the embryo caused by such gene mutations. Importantly, the DMDD programme includes analysis of placentas from these mutants. Through this uniquely comprehensive assessment, the team was able to show a significant co-occurrence of placental defects alongside abnormalities in the brain, heart and vascular system.

The co-first authors on the paper are Dr Vicente Perez-Garcia and Mrs Elena Fineberg. Dr Perez-Garcia, said: "Analysis of embryonic lethal mutants has largely focused on the embryo and not the placenta, despite its critical role in development. Of the mutations we've studied, far more than expected showed defects in the placenta and this is particularly true for mutations that cause death during the early stages of pregnancy. Intriguingly, our analysis also indicates that issues in the placenta often occur alongside specific defects in the embryo itself."

The senior researcher on the study was Dr Myriam Hemberger, Group Leader in Epigenetics at the Babraham Institute. Dr Hemberger, said: "Our data highlight the hugely under-appreciated importance of placental defects in contributing to abnormal embryo development and suggest key molecular nodes governing placentation. The importance of a healthy placenta has often been overlooked in these studies and it is important that we start doing more to understand its contribution to developmental abnormalities."

Dr Tim Mohun, Group Leader at the Crick, who performed the detailed morphological analysis of the embryos said: "These are fascinating findings and have only been uncovered because the DMDD programme has surveyed such a large number of genetic mutations that cause embryo death in mice. I'm sure there is much more to learn from systematic mining of DMDD data."

The paper 'Placentation defects are highly prevalent in embryonic lethal mouse mutants' is published in Nature.