First genetic link between reptile and human heart evolution

September 2, 2009,
Image: Wikimedia Commons

Scientists at the Gladstone Institute of Cardiovascular Disease have traced the evolution of the four-chambered human heart to a common genetic factor linked to the development of hearts in turtles and other reptiles.

The research, published in the September 3 issue of the journal Nature, shows how a specific protein that turns on genes is involved in heart formation in turtles, lizards and humans.

"This is the first genetic link to the of two, rather than one, pumping chamber in the heart, which is a key event in the evolution of becoming warm-blooded," said Gladstone investigator Benoit Bruneau, PhD, who led the study. "The gene involved, Tbx5, is also implicated in human , so our results also bring insight into human disease."

From an evolutionary standpoint, the reptiles occupy a critical point in heart evolution.

While bird and mammalian hearts have four chambers, frogs and other amphibians have three. "How did hearts evolve from three to four chambers?" Bruneau said. "The different reptiles offer a sort of continuum from three to four chambers. By examining them, we learned a lot about how the human heart chambers normally form."

He explained that with four chambers—two atria and two ventricles—humans and all other mammals have completely separate blood flows to the lungs and to the rest of the body, which is essential for us to be warm-blooded.

Embryo hearts show evolution of the heart from a three-chambered in frogs to a four-chambered in mammals. Credit: Zina Deretsky, National Science Foundation after Benoit Brueau, the Gladstone Institute of Cardiovascular Disease

When it comes to reptiles, such as turtles and , there is debate about whether they have one or two ventricles, which are the pumping chambers. "The main question for us to understand the evolution of the heart was to identify the true nature of these early reptile ventricles and to figure out what controls the separation of the heart into left and right sides," said Dr. Bruneau.

To better understand reptile heart evolution, Dr. Bruneau's team used modern to examine Tbx5. Mutations in the human gene that encodes Tbx5 result in congenital heart disease and, in particular, defects in the ventricular septum, the muscular wall that separates the ventricle into two sections. Tbx5 is a transcription factor, a protein that turns other genes on or off. In humans and other mammals, Tbx5 levels are high in the left ventricle and low in the right. The boundary of high and low levels is right where the septum forms to divide the ventricle into two parts. "Based on these observations," said Dr. Bruneau, "we thought Tbx5 was a good candidate as a key player in the evolution of septation."

The team looked at Tbx5 distribution in the turtle and the green anole lizard. During the early stages of heart formation in both reptiles, Tbx5 activity is found throughout the embryonic ventricular chamber. In the lizard, which forms only one ventricle, this pattern stays the same as the heart develops. However, in the turtle, which has a primitive septum that partially separates the ventricles into left and right sides, distribution of Tbx5 is later gradually restricted to the area of the left ventricle, resulting in a left-right gradient of Tbx5 activity. This meant that the gradient of Tbx5 forms later and less sharply in the turtle than in species with a clear septum, such as mammals, providing a tantalizing clue about how septation evolved.

The three-chambered frog heart mixes oxygenated and deoxygenated blood in the ventricle. Therefore, the body never receives fully oxygen-rich blood. In turtles, where a septum begins to form and separate the ventricles, the body receives slightly richer blood in oxygen. It is only in the warm-blooded model, in birds and mammals, that the two circulatory systems become fully separate sending low-pressure pumping to the lungs, and a high-pressure flow of blood to the rest of the body. In this model, the animal's muscles receive fully oxygenated blood. Credit: Credit: Zina Deretsky, National Science Foundation

They then wanted to determine whether Tbx5 was really a main regulator of septation or merely a bystander. Mice were genetically engineered to express Tbx5 at a moderate level throughout the developing heart, just like in turtle hearts. By mimicking the turtle pattern, mouse hearts now resembled turtle hearts. The offspring from these mice died young and had only a single ventricle. This striking result conclusively showed that a sharp line delineating an area of high level of Tbx5 is critical to induce formation of a septum between the two ventricles.

"This really nailed the importance of Tbx5 in patterning the heart to allow septation to occur," said Dr. Bruneau.

During evolution, new genetic regulatory elements evolved to tell the Tbx5 gene to form a sharp boundary of Tbx5 expression. This resulted in two ventricles. Researchers will now work to identify those genetic regulatory mechanisms during the evolution of reptiles. The work also has important implications for the understanding of congenital heart defects, which are the most common human birth defect, occurring in one out of every one hundred births worldwide. Humans born with only one pumping chamber, resembling frog hearts, suffer the highest mortality and require extensive surgery as newborns.

"Our study provides exciting new insights into the evolution of the heart, which had not been examined in over 100 years," Dr. Bruneau explained. "In a larger context, it provides good support for the concept that changes in the expression levels of various regulatory molecules are important in evolution. From these studies we also hope to understand further how defects in septation occur in humans with congenital disease."

Source: Gladstone Institutes (news : web)

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not rated yet Sep 02, 2009
zevkirsh, I disagree, the distribution of Tbx5 around the developing phenotypes heart is clearly seen as the control factor for both mammals and turtles. If anything, the article succeeds spectacularly well in isolating the genetic origins of 4-chambered hearts
not rated yet Sep 02, 2009
Makes you wonder how a 3 chambered heart could ever evovle into a 4 chambered heart, doesn't it? The formation of the septum is only one of a number of changes that has to happen simultaneously, like valves, heart beat rhythm. If there is a lack of co-ordinating changes the animal is left with a weak heart which would surely greatly prejudice its chances of survival, let alone reproducing.
not rated yet Sep 03, 2009
it would be cool if they could try the opposite now - see if they can cause 4-chamber separation in amphibians or reptiles just by adding this gene.
that would also test smiffy's point, which i am kinda skeptical about.
5 / 5 (1) Sep 03, 2009
Oh bloody hell the Spammer Returns. Only this time not a AASpammer but the key link is still the same.

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5 / 5 (1) Sep 03, 2009
So you found a new sponsor or is this simply your first ever reply?

5 / 5 (1) Sep 04, 2009
The formation of the septum is only one of a number of changes that has to happen simultaneously, like valves, heart beat rhythm.

It doesn't have to happen simultaneously. Parts can develop at different rates. This can be seen by looking at that turtle. It has a mix of parts and survive.

The full four chambered heart is only needed once the rest of the organism has adapted to having such a thing and becomes dependent upon it not just for periods of great exertion but all the time.

This looks to me to have occurred in a common ancestor of dinosaurs, crocodilians and mammal like reptiles.

5 / 5 (1) Sep 04, 2009
Yeah, I changed my mind about my comment after sleeping on it. Actually changed my mind a few times as I learn more and more about it. I'm posting this before I change it again.

Looking at the graphic of the turtle's heart it's obvious that the more the septum grows the more efficient the heart becomes - and the septum can grow as fast or as slow as it likes. Given this setup, advancing to a four chambered heart is bound to happen. The only limitation I can see is that the lung tissues should have their own independent blood supply (that's to say they must not depend, if they ever did, on the partially oxygenated blood coming through the pulmonary artery which will become less oxygenated over time as the septum grows.)

What I have found out in my travels in GoogleLand is that the right ventricle has a different kind of lining to it than the left, owing to the fact that the right is no longer in contact with oxygenated blood. The lining is tougher as a result.

" ventricular septation is accompanied by progressive coronary support to the heart and the replacement of spongy myocardium with compact tissue."

This might be an alternative explanation for the role of the gene, Tbx5. To replace the spongy tissue with the tougher stuff. Certainly the location of the gene seems to parallel that part of the lining which receives the least oxygenated blood and it advances around the lining as you would expect, as the septum grows. Removing the gene may have caused the mouse's septum to vanish if there was no spongy tissue to fall back on, as you might expect with a structure that never came into contact with oxygenated blood and therefore was always only compact tissue, at least on one side.

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