Placentation defects are highly prevalent in embryonic lethal mouse mutants

Vincente Perez-Garcia, Elena Fineberg, Robert Wilson, Alexander Murray, Cecilia Icoresi Mazzeo, Catherine Tudor, Arnold Sienerth, Jacqueline White, Elizabeth Tuck, Edward Ryder, Diane Gleason, Himsha Beltran, Emma Siragher, Hannah Wardle-Jones, Nicole Staudt, Neha Wali, John Collins, Stefan Geyer, Elisabeth Busch-Nentwich, Antonella Galli, James Smith, Elizabeth Robertson, David Adams, Wolfgang Weninger, Timothy Mohun and Myriam Hemberger

Nature 2018. 555: 463-468.


Large-scale phenotyping efforts have demonstrated that approximately 25–30% of mouse gene knockouts cause intrauterine lethality. Analysis of these mutants has largely focused on the embryo and not the placenta, despite the crucial role of this extraembryonic organ for developmental progression. Here we screened 103 embryonic lethal and sub-viable mouse knockout lines from the Deciphering the Mechanisms of Developmental Disorders program for placental phenotypes. We found that 68% of knockout lines that are lethal at or after mid-gestation exhibited placental dysmorphologies. Early lethality (embryonic days 9.5–14.5) is almost always associated with severe placental malformations. Placental defects correlate strongly with abnormal brain, heart and vascular development. Analysis of mutant trophoblast stem cells and conditional knockouts suggests that a considerable number of factors that cause embryonic lethality when ablated have primary gene function in trophoblast cells. Our data highlight the hugely under- appreciated importance of placental defects in contributing to abnormal embryo development and suggest key molecular nodes that govern placenta formation.

Our Thoughts on This Paper

The placenta is a feto-maternal organ of primarily fetal origin. Labyrinth and junctional zones of the placenta are fetal-derived while the decidual zone is maternally derived. A fully vascularized placenta ensures adequate fetal and maternal nutrient and gas exchange thus placental defects could affect embryonic development. While there are a large number of mouse strains that are embryonic lethal, whether these are embryonic or placentation defects had previously not been comprehensively studied. In this report, Perez-Garcia et al. demonstrate the importance of placental development by identifying that placental dysmorphologies are associated with more than half of tested strains with embryonic lethality. When a strain is embryonic lethal prior to E14.5, placental defects were found in nearly all strains.

To separate whether placentation defects are independent of embryonic defects, candidate genes were tested for in vitro placentation using trophoblast stem cells, finding that two of three embryonic lethal gene deletions in the trophoblasts also had defective markers of stem cell renewal and in vitro differentiation into mature placental tissues. To test these findings in an in vivo system, the authors used conditional knockouts to demonstrate that for one of the three genes tested, embryonic development was partially normalized when placental gene expression was intact but embryonic tissues were ablated. This report highlights the importance of proper placentation and how placental development or lack thereof can alter embryonic development. This argues for a broader consideration of placental development when considering the embryonic lethality of some variants.

Written by Noura El Habbal on March 28, 2019.


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