Strange gut feeling

The lab of Alexander Meissner reveals the fate of extraembryonic cells in developing intestinal organs.

During development, extraembryonic cells contribute to the formation of structures outside of the embryo. The additional presence of these extraembryonic cells in the developing gut has long puzzled scientists. In a new study in Nature Cell Biology, Alexander Meissner’s lab now provides new insights into the developmental fate and molecular characteristics of these cells.

In early mammalian development, embryonic cells, which form the developing organism, segregate from extraembryonic cells, which form supporting structures. The prominent extraembryonic tissues are the yolk sac and the placenta, which provide nutrients and oxygen to the developing fetus but are discarded after birth. A surprising exception to the conventional embryonic-extraembryonic separation happens in the developing gut, where it has been shown in mouse models that extraembryonic cells mix with embryonic cells.

“An important question we have now addressed is what happens to these extraembryonic cells during later stages of organogenesis,” says Julia Batki, a postdoctoral researcher in the Meissner lab and one of the study's first authors. “Here, we have shown that they are specifically eliminated by programmed cell death and have identified the protein p53 as the central effector”.

Love thy neighbor

The scientists began by labeling extraembryonic mouse cells with a fluorescent marker to observe them throughout development. Initially, detecting the fluorescent signal gave the impression that extraembryonic cells persist longer than previously reported. However, the scientists soon realized that something wasn't adding up. “We recognized that we needed to revise our approach and label both embryonic and extraembryonic cells," says Sara Hetzel, the other first author and postdoc in the Meissner lab. “What we initially observed were actually the remnants of extraembryonic cells that had been taken up by embryonic cells." It turns out that the extraembryonic gut cells die by programmed cell death. The scientists were able to show that this depends on a protein called p53, which is also a known tumor suppressor. The remains are engulfed by neighboring gut cells in a process called phagocytosis.

Transcriptionally similar – epigenetically different

The team then turned their attention to the differences in the transcriptomes and epigenetic marks between embryonic and extraembryonic cells. They confirmed previous findings that extraembryonic cells develop towards a state where they express similar genes to their embryonic counterparts. “However, when we looked at the epigenetic landscape, we found that extraembryonic cells retain a molecular memory of their origin through DNA methylation marks," explains Sara Hetzel. DNA methylation is a chemical modification of DNA that changes its activity without altering the DNA sequence itself. "Fascinatingly, even in p53 mutants, where extraembryonic cells remain much longer than they would during normal development, the cells retain their original signature and can even contribute to later organ development," adds Julia Batki. Why extraembryonic cells become part of the developing gut in the first place and their putative physiological roles remain important questions for future research.