Reptilian heart development and the molecular basis of cardiac chamber evolution

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Abstract
Birds, mammals and crocodiles have hearts with two separate ventricles, servicing separate pulmonary and systemic circulations. Amphibians have just one ventricle, but in most reptiles, the situation is unclear. A new embryological study of a lizard (the green anole) and a turtle (the slider turtle) shows that the division of an ancestral single ventricle into two chambers is related to the expression of the T-box transcription factor Tbx5. In embryonic birds and mammals, Tbx5 expression is restricted to precursors of the left ventricle. In turtles and lizards, Tbx5 is initially expressed throughout the ventricle, but in turtles (though not lizards) it is later restricted to the left side of the chamber. This identifies altered Tbx5 expression as a possible evolutionary force driving embryonic heart patterning to provide the key adaptation to high-energy terrestrial life, the fully septated heart. In line with this idea, mice in which Tbx5 function is lost or expanded develop a single chamber lacking distinct identity. The hearts of birds, mammals and crocodiles have two ventricles serving separate pulmonary and systemic circulations, whereas the hearts of amphibians have only one ventricle. In most reptiles, however, the situation is unclear, which is of interest in the context of the evolution of cardiac septation. Here, gene expression in the developing ventricles of two reptiles is analysed; the results suggest a role for the T-box transcription factor Tbx5. The emergence of terrestrial life witnessed the need for more sophisticated circulatory systems. This has evolved in birds, mammals and crocodilians into complete septation of the heart into left and right sides, allowing separate pulmonary and systemic circulatory systems, a key requirement for the evolution of endothermy1,2,3. However, the evolution of the amniote heart is poorly understood. Reptilian hearts have been the subject of debate in the context of the evolution of cardiac septation: do they possess a single ventricular chamber or two incompletely septated ventricles4,5,6,7? Here we examine heart development in the red-eared slider turtle, Trachemys scripta elegans (a chelonian), and the green anole, Anolis carolinensis (a squamate), focusing on gene expression in the developing ventricles. Both reptiles initially form a ventricular chamber that homogenously expresses the T-box transcription factor gene Tbx5. In contrast, in birds and mammals, Tbx5 is restricted to left ventricle precursors8,9. In later stages, Tbx5 expression in the turtle (but not anole) heart is gradually restricted to a distinct left ventricle, forming a left–right gradient. This suggests that Tbx5 expression was refined during evolution to pattern the ventricles. In support of this hypothesis, we show that loss of Tbx5 in the mouse ventricle results in a single chamber lacking distinct identity, indicating a requirement for Tbx5 in septation. Importantly, misexpression of Tbx5 throughout the developing myocardium to mimic the reptilian expression pattern also results in a single mispatterned ventricular chamber lacking septation. Thus ventricular septation is established by a steep and correctly positioned Tbx5 gradient. Our findings provide a molecular mechanism for the evolution of the amniote ventricle, and support the concept that altered expression of developmental regulators is a key mechanism of vertebrate evolution.