Placenta defects critical factor in prenatal deaths

Research in mice reveal genes whose roles appear to be vital in developing healthy placentas

Babraham Institute

The placentas of two mouse embryos part way through development: unaffected embryo on the left and embryo with a mutation in the Nubpl gene on the right. The Nubpl gene affects development and leads to pre-natal death. The green staining on the left image show the exchange surface where nutrients are transferred between the mother and embryo, along with the red staining of cells underlying this exchange. The exchange surface and most of the cells underneath are missing in the embryo on the right. Image provided by the Babraham Institute

The role of the placenta in healthy fetal development is being seriously under-appreciated according to a new paper published today (14th March). The study was part of the Wellcome-funded “Deciphering the Mechanisms of Developmental Disorders (DMDD)” consortium (dmdd.org.uk). Dr Myriam Hemberger at the Babraham Institute, Cambridge led the research, working with colleagues at the Wellcome Sanger Institute, Cambridge, the Francis Crick Institute, London, the University of Oxford and the Medical University of Vienna, Austria. Writing in the journal Nature, the team studied 103 genetic mutations in mice that cause embryos to die before birth. The results showed that the majority, almost 70 per cent, 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, and 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, i.e. changes to their shape and structure. Around one-third of all gene mutants studied in mouse are lethal or subviable (i.e. 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.

“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.”

Dr Vicente Perez-Garcia Co-first author on the paper with Mrs Elena Fineberg from the Babraham Institute, Cambridge

“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 Myriam Hemberger Senior researcher on the study and Group Leader in Epigenetics at the Babraham Institute

The placenta-focussed aspect of the DMDD project was carried out at the Babraham Institute where all mutant placentas were analysed and characterised for their morphological defects. The Institute researchers also carried out work using mouse placental stem cells to understand further the functional roles of particular genes in the development of this organ. The detailed morphological analysis of embryos was performed by Dr Tim Mohun at the Francis Crick Institute together with colleagues at the Division of Anatomy, Medical University of Vienna, Austria.

The mutant mouse lines were produced and bred at the Wellcome Sanger Institute.

“Large-scale mouse genetics has been at the forefront of scientific discovery as exemplified by this paper showing a key role for the placenta in prenatal death. The effect of genetic changes on the placenta had not been systematically studied before and the mouse DMDD programme was a vital and integral part of this research that could lead to further research to better understand problems with human placental development.”

Dr David Adams Group Leader at the Wellcome Sanger Institute

More information

Publication Reference

Perez-Garcia Vicente, Fineberg Elena et al. (2018) Placentation defects are highly prevalent in embryonic lethal mouse mutants. Nature DOI: 10.1038/nature26002

Research Funding

Work at the Babraham Institute is possible thanks to the Biotechnology and Biological Sciences Research Council (BBSRC). This work is part of the Wellcome Trust Strategic Award ‘Deciphering the Mechanisms of Developmental Disorders (DMDD)’.