Embryonic development in slow motion

Date:
August 27, 2021
Source:
ETH Zurich
Summary:
Roe deer are among the few mammals whose embryos go into a
particularly long period of dormancy. Using modern molecular
methods, researchers have shown for the first time what exactly
happens in the embryo during this phase. They have identified
signals that control the embryo`s awakening.



FULL STORY ========================================================================== Everyone is familiar with the roe deer, either from crossword puzzles
or from real-life encounters during a jog or a hike in the forest:
majestic creatures with elegant big black eyes.


==========================================================================
As common as roe deer may seem in Swiss forests, one of their
characteristics is unique among deer species. After mating and
fertilisation of the egg in midsummer, the pinhead-sized embryo
does not implant in the uterus, but enters into a period of dormancy,
called embryonic diapause. This period lasts for over four months until December. Only then does the embryo continue its development at normal
pace and implants in the uterus. In May, after four and a half months of
"real" gestation, the doe gives birth to one to three fawns.

Although the phenomenon has been known for more than 150 years, it still puzzles. Various forms of embryonic diapause are known to occur in over
130 mammalian species. However, they rarely last as long as observed in
the roe deer. And, most importantly, almost no other species shows such
a pronounced, continuous deceleration instead of a complete halt. In
mice, scientists can artificially induce diapause. However, in roe deer
it is still unclear which factors control diapause while keeping the
embryo alive.

The research group led by Susanne Ulbrich, Professor of Animal Physiology
at ETH Zurich, has been investigating the mystery of roe deer diapause for
some time. In a new study, the researchers show which molecular processes
take place in the embryo while it is dormant: embryonic cells continue to divide during diapause, albeit very slowly. The number of cells, including embryonic stem cells, doubles only every two to three weeks. The study,
which has just been published in the journal PNAS, involved not only the
ETH group, but also researchers from the Universities of Zurich and Bern,
as well as German and French research institutions.

Gene transcripts and signalling molecules studied To answer the question
of what prevents the embryonic cells from dividing at a normal pace,
the researchers first examined the molecular composition of the uterine
fluid. Next, they took a closer look at the transcriptome, i.e., the
sum of all messenger RNA molecules, of the embryos and the uterine
epithelial cells.



==========================================================================
In the uterine fluid, the researchers found signalling substances
that could regulate the cell division rate. The amino acid serine was particularly conspicuous. The ETH researchers showed that towards the
end of diapause, the concentration of certain amino acids in the uterine
fluid changes. The cell proliferation rate then concomitantly returns
to a normal rate.

This process involves the molecular complex mammalian target of rapamycin (mTOR). mTOR reacts to amino acids and plays a crucial role in many
metabolic signalling pathways in mammalian cells, including those
associated with cancer.

mTORC1, for example, regulates protein synthesis and thus cell growth
and division.

According to the new findings, the activity of only mTORC1, but not
mTORC2, is suppressed in roe deer embryos throughout diapause. This is
in contrast to diapausing mice, where cell division is completely halted
upon inhibition of both mTORC1 and mTORC2.

Towards the end of diapause, the significant increase in the amino acid
level in the uterine fluid activates mTORC1. This, in turn, increases the expression of metabolic and cell cycle genes, driving embryo development forwards.

Meanwhile, since mTORC2 is not inhibited during diapause in roe deer
embryos, the researchers hypothesise that this could explain why cell
division slowly continues.

In this study, the researchers did not investigate whether other
signalling molecules are involved alongside the various amino acids. It
also remains unclear whether the amino acids are actually responsible for
the resumption of embryonic development or whether the embryo itself
also secretes molecules that act on maternal cells and signalling
pathways. The embryo may indicate its presence to its mother through
specific signalling molecules. Ulbrich would like to close this knowledge
gap in future studies.

New light on reproductive biology These new findings shed light on
reproductive and developmental biology in general. One fundamental
question is how pregnancy is established in mammals.

For example, in women and in domestic cattle, embryos often fail to
implant in the uterus and die. "This has to do with complex interactions between the embryo and the mother," Ulbrich says.

She adds that a successful pregnancy calls for precise timing. The embryo
must make itself known at the right time through appropriate (molecular) signals and interrupt the mother's cycle. "We want to better understand
this interaction between embryo and mother," Ulbrich explains. For
this, she says, the roe deer is an ideal model. Embryonic development
in roe deer is very similar to that of cattle but takes place in slow
motion. "This allows us to better temporally resolve the sequence of
events and find causal relationships." The findings could also help
improve in vitro fertilisation in humans so that embryos may no longer
need to be frozen. Moreover, natural factors could be used to control
the rate at which cells, including embryonic stem cells, divide.

========================================================================== Story Source: Materials provided by ETH_Zurich. Original written by
Peter Ru"egg. Note: Content may be edited for style and length.


========================================================================== Journal References:
1. van der Weijden VA, Bick JT, Bauersachs S, Rueegg AB, Hildebrandt
TB,
Goeritz F, Jewgenow K, Giesbertz P, Daniel H, Derisoud E,
Chavatte- ​Palmer P, Bruckmaier RM, Drews B, Ulbrich
SE. Amino acids activate mTORC1 to release roe deer embryos
from decelerated proliferation during diapause. PNAS, 2021 DOI:
10.1073/pnas.2100500118
2. AB Ru"egg, S Bernal, FN Moser, I Rutzen, SE Ulbrich. Trophectoderm
and
embryoblast proliferate at slow pace in the course of embryonic
diapause in the roe deer (Capreolus capreolus). Bioscientifica
Proceedings, 2020; DOI: 10.1530/biosciprocs.10.013 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210827121505.htm

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