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A study from the University of Vienna reveals that sea anemones use a molecular mechanism known from bilaterian animals to form their back-to-belly body axis. This mechanism ("BMP shuttling") enables cells to organize themselves during development by interpreting signaling gradients.

The findings, in Science Advances, suggest that this system evolved much earlier than previously assumed and was already present in the common ancestor of cnidarians and bilaterians.

Most animals exhibit bilateral symmetry—a body plan with a head and tail, a back and belly, and left and right sides. This body organization characterizes the vast group known as Bilateria, which includes animals as diverse as vertebrates, insects, mollusks and worms.

In contrast, cnidarians, such as jellyfish and sea anemones, are traditionally described as radially symmetric, and indeed jellyfish are. However, the situation is different is the sea anemones: despite superficial radiality, they are bilaterally symmetric—first at the level of gene expression in the embryo and later also anatomically as adults.

This raises a fundamental evolutionary question: did bilateral symmetry arise in the common ancestor of Bilateria and Cnidaria, or did it evolve independently in multiple animal lineages?

Researchers at the University of Vienna have addressed this question by investigating whether a key developmental mechanism called BMP shuttling is already present in cnidarians.

Shuttling for development

In bilaterian animals, the back-to-belly axis is patterned by a signaling system involving Bone Morphogenetic Proteins (BMPs) and their inhibitor Chordin.

BMPs act as molecular messengers, telling embryonic cells where they are and what kind of tissue they should become. In bilaterian embryos, Chordin binds BMPs and blocks their activity in a process called "local inhibition."

At the same time, in some but not all bilaterian embryonic models, Chordin can also transport bound BMPs to other regions in the embryo, where they are released again—a mechanism known as "BMP shuttling."

Animals as evolutionarily distant as sea urchins, flies and frogs use BMP shuttling, however, until now it has been unclear whether they all evolved shuttling independently or inherited it from their last common ancestor some 600 million years ago.

Both local inhibition and BMP shuttling create a gradient of BMP activity across the embryo. Cells in the early embryo detect this gradient and adopt different fates depending on BMP levels. For example, in vertebrates, the central nervous system forms where BMP signaling is lowest, kidneys will develop at intermediate BMP signaling levels, and the skin of the belly will form in the area of maximum BMP signaling.

This way, the body's layout from back to belly is established. To find out whether BMP shuttling by Chordin represents an ancestral mechanism for patterning the back to belly axis, the researchers had to look at bilaterally symmetric animals outside Bilateria—the sea anemones.

An ancient blueprint

To test whether sea anemones use Chordin as a local inhibitor or as a shuttle, the researchers first blocked Chordin production in the embryos of the model sea anemone Nematostella vectensis.

In Nematostella, unlike in Bilateria, BMP signaling requires the presence of Chordin, so, without Chordin, BMP signaling ceased and the formation of the second body axis failed. Chordin was then reintroduced into a small part of the embryo to see if it could restore axis formation.

BMP signaling resumed—but it was unclear whether this was because Chordin simply blocked BMPs locally, allowing a gradient to form from existing BMP sources, or because it actively transported BMPs to distant parts of the embryo, shaping the gradient more directly.

To answer this, two versions of Chordin were tested—one membrane-bound and immobile, the other diffusible. If Chordin acted as a local inhibitor, both the immobile and the diffusible Chordin would restore BMP signaling on the side of the embryo opposite to the Chordin-producing cells. However, only diffusible Chordin can act as a BMP shuttle.

The results were clear: only the diffusible form was able to restore BMP signaling at a distance from its source, demonstrating that Chordin acts as a BMP shuttle in sea anemones—just as it does in flies and frogs.

A shared strategy across over 600 million years of evolution?

The presence of BMP shuttling in both cnidarians and bilaterians suggests that this molecular mechanism predates their evolutionary divergence some 600–700 million years ago.

"Not all Bilateria use Chordin-mediated BMP shuttling, for example, frogs do, but fish don't, however, shuttling seems to pop up over and over again in very distantly related animals, making it a good candidate for an ancestral patterning mechanism. The fact that not only bilaterians but also sea anemones use shuttling to shape their body axes, tells us that this mechanism is incredibly ancient," says David Mörsdorf, first author of the study and postdoctoral researcher at the Department of Neurosciences and Developmental Biology at the University of Vienna.

"It opens up exciting possibilities for rethinking how body plans evolved in early animals."

Grigory Genikhovich, senior author and group leader in the same department, adds, "We might never be able to exclude the possibility that bilaterians and bilaterally symmetric cnidarians evolved their bilateral body plans independently.

"However, if the last common ancestor of Cnidaria and Bilateria was a bilaterally symmetric animal, chances are that it used Chordin to shuttle BMPs to make its back-to-belly axis. Our new study showed that."