Rewrite the text books!

We know alot about how embryos develop, but how they implant into the uterus - has remained a mystery. Now, scientists from Cambridge have discovered a way to study and film this 'black box' of development.

Their results - which will lead to the rewriting of biology text books worldwide - are published in the journal Cell.

Embryo development in mammals occurs in two phases. During the first phase, pre-implantation, the embryo is a small, free-floating ball of cells called a blastocyst. In the second, post-implantation, phase the blastocyst embeds itself in the mother's uterus.

While blastocysts can be grown and studied outside the body, the same has not been true from implantation onward. And because embryos are so closely connected to their mothers, implantation has also been difficult to study in the womb.

According to study author Professor Magdalena Zernicka-Goetz of the University of Cambridge: "We know a lot about pre-implantation, but what happens after implantation - and particularly the moment of implantation - is an enigma."

Scientists are interested in implantation because the embryo undergoes huge changes in such a short space of time.

"During these two days, it goes from a relatively simple ball to a much larger, more complex cup-like structure, but exactly how that happens was a mystery - a black box of development. That is why we needed to develop a method that would allow us to culture and study embryos during implantation," she explained.

Working with mouse cells, Professor Zernicka-Goetz and her colleague Dr Ivan Bedzhov succeeded in creating the right conditions outside the womb to study the implantation process.

To be able to support development, they created a system comprising a gel and medium that, as well as having the right chemical and biological properties, was of similar elasticity to uterine tissue. Crucially, this gel was transparent to optical light, allowing then to film the embryo during implantation.

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This new method revealed that on its way from ball to cup shape — the blastocyst becomes a 'rosette' of wedge-shaped cells. A structure never before seen by scientists.

"It's a beautiful structure. This rosette is what a mouse looks like on the 4th day of its life, and most likely what we look like on the 7th day of ours, and it's fascinating how beautiful we are then, and how these small cells organise so perfectly to allow us to develop."

As well as answering a fundamental question in developmental biology, the new method will allow scientists to study embryo growth and development at implantation for the first time.

This could help improve IVF success, and extend our knowledge of stem cells, perhaps advancing their use in regenerative medicine.

The findings also mean developmental biology text books will need rewriting.

"The text books make an educated guess of what happened during this part of development, but we now know that what I learned and what I teach my students about this — was totally wrong," adds Professor Zernicka-Goetz.

Abstract — Open access funded by Wellcome Trust
When in mammalian development cells first start to differ from each other and whether these first differences play any role in cell-fate specification remain key open questions. In many model systems, initiation of cell-fate specification stems from heterogeneity between the blastomeres of the early embryo, but whether this might also be the case in mammals remains unknown. The first cell-fate specification in the mammalian embryo leads to the separation of embryonic and extra-embryonic lineages. The embryonic lineage is pluripotent and will give rise to the fetus, while the extra-embryonic lineages will differentiate into supportive structures critical for embryo implantation and fetal development, the placenta, and yolk sac (Takaoka and Hamada, 2012, Zernicka-Goetz et al., 2009).

In conclusion, we suggest that highly heterogeneous expression of several Oct4 and/or Sox2 targets within the 4-cell embryo, regulated by differential activity of CARM1, creates heterogeneities that bias cell fate toward either an embryonic (pluripotent) or extra-embryonic (differentiating) fate. We further suggest that the highly heterogeneous expression of Sox21 is one of a number of mechanisms available to the embryo to direct cell fate. Our findings that several Oct4 and Sox2 target genes are overrepresented in the subset of highly variable genes at the 4-cell stage and that Sox21 is co-regulated with other transcription factors, such as Nanog and Esrrb, supports this hypothesis. Thus, if a single source of heterogeneity were to be removed, the embryo could compensate for this loss. In summary, our results indicate that heterogeneous gene expression as early as the 4-cell stage initiates cell-fate decisions.

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Mar 30, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

This rosette is what a mouse looks like on the 4th day of its life
from video Credit: Magdalena Zernicka-Goetz and Ivan Bedzhov



(A) Development from fertilized egg (zygote) to blastocyst following three lineages:
epiblast (EPI; BLUE), primitive endoderm (PE, RED), and trophectoderm (TE, GREEN).
Mechanism(s) initiating cell-fate remains unknown (reviewed in Zernicka-Goetz et al., 2009).