Comparing pumps.

Comparative evolutionary studies have greatly aided our understanding of how the heart develops. Two recent articles from Benoit Bruneau’s laboratory reveal the power of the so-called evo-devo approach and provide yet further details of development, both of the heart itself and of the cells that build it. Thanks to our many and varied primitive cousins, developmental biologists are gaining a good picture of the conserved genes and pathways controlling heart development.1 It appears that Natural Selection’s fiddly fingers have taken a basic set of genes and pathways—capable of giving rise to the simple peristaltic pumps of insects, for example—and then tweaked, tuned, and expanded them to build hearts that meet the needs of increasingly complex multicellular organisms. Heart evolution has not just been about meeting needs, though. It has also been a driving force that has enabled increased complexity and new evolutionary adaptations, for example, the adaptation to warm-bloodedness. Endotherms require more oxygen than their cold-blooded counterparts to supply their high metabolic activity. “One of the major evolutionary adaptations that allowed mammals to become warm-blooded was the formation of the fourchambered heart,” says Benoit Bruneau (Gladstone Institute of Cardiovascular Disease, San Francisco, Ca). Four chambers means no mixing of deoxygenated and oxygenated blood, and thus, more oxygen gets to the tissues. This adaptation was not sufficient alone, however, Bruneau explains. “You need a certain lung structure. There’s certain changes to the breathing apparatus that are necessary, and other things as well that have to happen.” But the point is, he says, “None of that can happen if you don’t have a fourchambered heart.” Cold-blooded fish and amphibians have three-chambered hearts, two atria and one ventricle. Reptiles are a mixed bag with some, like crocodiles and alligators, having fourchambered hearts and others, like lizards, having threechambered hearts. The crocodilian four-chambered heart has led people to speculate that crocodile ancestors may have been warmblooded. But Bruneau thinks not. “My interpretation of the crocodile and alligator hearts,” he says, “is that they’ve sort of overshot their evolution: the heart part has moved ahead but the rest hasn’t caught up.” The fourth chamber has arisen via the separation of one large ventricle into two. In animals in which this occurs, a transcription factor called Tbx5 concentrates in the prospective left ventricle during heart development. Bruneau’s team wondered what the pattern of Tbx5 mRNA expression would look like in the three-chambered hearts of non-crocodilian reptiles. They chose to compare a turtle with a lizard.2 Turtle hearts are interesting because, although they have just one large ventricle, there is evidence of a primitive interventricular septum (IVS)-like structure. Lizards, on the other hand, are considered evolutionarily less complex creatures and have no hint of an IVS. At early stages of heart development in the turtle, Trachemys scripta elegans, and the lizard, Anolis carolinenis, Tbx5 was expressed broadly across the heart. At comparable stages in the chick and mouse, however, Tbx5 expression was tightly concentrated on the left side of the heart. Interestingly, later in the development of the turtle heart, Tbx5’s expression pattern changed. It diminished on the right side of the large single ventricle and increased on the left. Target genes of Tbx5 (Bmp10 and Nppa) were also restricted to the left side. The gradient of Tbx5 expression in the turtle heart was not as steep as that in chicken or mouse, and it occurred at a later stage of embryogenesis. This perhaps explains why only a partial IVS-like structure forms in the turtle heart. In the lizard, the distribution of Tbx5 remained broad. Although this comparative study provided a pleasing correlation between Tbx5 expression patterns and the formation of the IVS, the question remained as to whether this gradient of Tbx5 expression was actually driving IVS patterning. The authors went some way to answering this by removing the Tbx5 gradient in developing mouse hearts. They conditionally deleted Tbx5 from the embryonic ventricles and also misexpressed Tbx5 across the entire early ventricle. Both of these experiments resulted in the loss of the IVS and the development of one large ventricle. Christine “Kricket” Seidman (Harvard Medical School, Boston, Ma) describes Bruneau’s study as, “a creative integration of evolutionary and developmental biology, which provides new insights into cardiac septation.” Seidman explains, “Atrial and ventricular septal defects are among the most common of human congenital heart malformations.” Thus, she says, “Understanding this important process should help to elucidate why human patients often have defects in septation.” Seidman’s laboratory had first shown that mutations in TBX5 in humans could cause septal defects,3 and “now it seems likely that mutations in any factors that play a part in the level or localization of Tbx5 expression might also lead to malformation of the IVS,” Bruneau says. Tbx5 functions in the development of other systems and organs besides the heart. Even within the heart, Tbx5 has a number of roles. Two articles published in Nature Genetics recently revealed that human TBX5 variants affect heart conduction in the general population,4,5 a role that had The opinions expressed in News and Views are not necessarily those of the editors or of the American Heart Association. (Circ Res. 2010;106:809-811.) © 2010 American Heart Association, Inc.