The evolutionary origin of cardiac chambers.

Identification of cardiac mechanisms of retinoic acid (RA) signaling, description of homologous genetic circuits in Ciona intestinalis and consolidation of views on the secondary heart field have fundamental, but still unrecognized implications for vertebrate heart evolution. Utilizing concepts from evolution, development, zoology, and circulatory physiology, we evaluate the strengths of animal models and scenarios for the origin of vertebrate hearts. Analyzing chordates, lower and higher vertebrates, we propose a paradigm picturing vertebrate hearts as advanced circulatory pumps formed by segments, chambered or not, devoted to inflow or outflow. We suggest that chambers arose not as single units, but as components of a peristaltic pump divided by patterning events, contrasting with scenarios assuming that chambers developed one at a time. Recognizing RA signaling as a potential mechanism patterning cardiac segments, we propose to use it as a tool to scrutinize the phylogenetic origins of cardiac chambers within chordates. Finally, we integrate recent ideas on cardiac development such as the ballooning and secondary/anterior heart field paradigms, showing how inflow/outflow patterning may interact with developmental mechanisms suggested by these models.

A caudorostral wave of RALDH2 conveys anteroposterior information to the cardiac field.

Establishment of anteroposterior (AP) polarity is one of the earliest decisions in cardiogenesis and plays an important role in the coupling between heart and blood vessels. Recent research implicated retinoic acid (RA) in the communication of AP polarity to the heart. We utilized embryo culture, in situ hybridization, morphometry, fate mapping and treatment with the RA pan-antagonist BMS493 to investigate the relationship between cardiac precursors and RA signalling. We describe two phases of AP signalling by RA, reflected in RALDH2 expression. The first phase (HH4-7) is characterized by increasing proximity between sino-atrial precursors and the lateral mesoderm expressing RALDH2. In this phase, RA signalling is consistent with diffusion of the morphogen from a large field rather than a single hot spot. The second phase (HH7-8) is characterized by progressive encircling of cardiac precursors by a field of RALDH2 originating from a dynamic and evolutionary-conserved caudorostral wave pattern in the lateral mesoderm. At this phase, cardiac AP patterning by RA is consistent with localized action of RA by regulated activation of the Raldh2 gene within an embryonic domain. Systemic treatment with BMS493 altered the cardiac fate map such that ventricular precursors were found in areas normally devoid of them. Topical application of BMS493 inhibited atrial differentiation in left anterior lateral mesoderm. Identification of the caudorostral wave of RALDH2 as the endogenous source of RA establishing cardiac AP fates provides a useful model to approach the mechanisms whereby the vertebrate embryo confers axial information on its organs.