Robust gene networks from the depths of our evolutionary history

Date:
September 29, 2021
Source:
University of Basel
Summary:
A sophisticated system guides the development of our
limbs. Researchers have shed new light on the genetic toolkit used
during evolution to create a range of different extremities such
as fins, wings, hooves, toes and fingers.



FULL STORY ==========================================================================
A sophisticated system guides the development of our limbs. Researchers
at University of Basel have shed new light on the genetic toolkit used
during evolution to create a range of different extremities such as fins, wings, hooves, toes and fingers.


==========================================================================
Much can go wrong when a fertilized egg develops into an embryo and
ultimately gives rise to a newborn as mutations in the genome that affect development are relatively common. The fact that embryonic development is usually flawless for humans and animals is due to the fact that genetic programs are controlled by series of gene circuits that can back one
another up in a self-regulatory fashion.

This robustness of developmental programs is a key interest of the
research group led by Professor Rolf Zeller and PD. Dr. Aime'e Zuniga
at the Department of Biomedicine, University of Basel. They seek to gain insights into this process studying a key regulator of limb development,
a protein called "Gremlin1." This protein stops cells from forming bones
too early and functions in fine tuning the activity of several signaling networks by connecting them with one another. Most importantly, Gremlin1
is responsible for the correct formation of the so called limb buds, which
are the tiny embryonic structure that will give rise to our extremities.

A network secures perfect development Studies using mouse embryos have
enabled researchers to decipher yet another level of regulation --
and robustness -- of this developmental program. In the scientific
journal Nature Communications, they describe a series of "switches"
embedded in the genome of all vertebrates which ensures that the correct
amount of Gremlin1 is produced at the right place. These switches are
called "enhancers." Zuniga compares the system that she and her team
are investigating with a room's lighting system that is controlled by
a series of switches. The light enables one to read the instructions
to build correctly formed extremities. "In the beginning, we did not
know what each individual switch contributes to lighting the room,"
the researcher explains. "There could be a master switch that turns
off all lights, making the instructions impossible to read. Instead,
we now know that all switches contribute to the lighting system: if one
switch is broken the amount of light is only marginally or not at all
affected and the information can still be read. This is why the system
is so robust. On the other hand, once too many switches are broken,
too little of the information can be read, and in the worst case none
at all." Indeed, analysis by PhD student Jonas Malkmus and colleagues
showed that individual switches can be inactivated without disrupting
Gremlin1 or the development of extremities. However, below a certain
threshold of functioning switches, the system fails and malformations
occur. "The multiple safeguards in the system explain why birth defects
due to genetic alterations in Gremlin1 regulation are extremely rare,"
says Malkmus.

Stability with potential for change Next, the researchers set out to
identify the evolutionary roots of this robust series of switches. They
found that the core of this series of switches that ensures the
correct amount and distribution of Gremlin1 in human embryos existed
in fishes already more than 400 million years ago. "This shows that
evolution already had the toolkit for developing extremities even
before fins evolved into legs and the first animals went ashore,"
explains Zuniga. What changed over the course of evolution was the
activity of individual enhancers and, as a result, the distribution of Gremlin1. "The activity of the genetic switches and the distribution of Gremlin1 in limb buds prefigures their subsequent development into fins,
wings, hooves or hands and feet," explains Zeller.

If only one switch would regulate the production of Gremlin1,
then the evolutionary pressure to keep this switch exactly as it is
would be huge. "A system with many switches ensures that the system
does not easily fail," says Zuniga. "And it gives evolution room for
change." Therefore, individual switches have been able to change without significant pressure, and this has played a part in the development of
a wide range of extremities during the history of evolution.

The study received financial support from the Swiss National Science
Foundation and an Advanced Grant of the European Research Council ERC.

========================================================================== Story Source: Materials provided by University_of_Basel. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Jonas Malkmus, Laure`ne Ramos Martins, Shalu Jhanwar, Bonnie
Kircher,
Victorio Palacio, Rushikesh Sheth, Francisca Leal, Amandine
Duchesne, Javier Lopez-Rios, Kevin A. Peterson, Robert Reinhardt,
Koh Onimaru, Martin J. Cohn, Aime'e Zuniga, Rolf Zeller. Spatial
regulation by multiple Gremlin1 enhancers provides digit development
with cis- regulatory robustness and evolutionary plasticity. Nature
Communications, 2021; 12 (1) DOI: 10.1038/s41467-021-25810-1 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210929101840.htm

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