Maija H. Zile
Experimental Biology and Medicine 229:598-606 (2004)
Figure 1. Ventral view of normal (N) and vitamin A–deficient (VAD) quail embryos at ~72 hrs of development. Note the looped heart (arrow) and the extensive vascular networks (arrowheads) in the normal embryo. The vitelline veins link the normal embryo to the extraembryonal circulation. In the VAD embryo, the heart does not loop, is enlarged and ballooned, has no chambers, and is closed at the site of the inflow tract. The extraembryonal vascular networks do not form in the VAD embryo, thus there is no circulation. The VAD embryo will die by ~3.5 days of development. There are no survivors.
Vitamin A is required throughout the life cycle, including crucial stages of embryonic and fetal development. With the identification of retinoic acid–specific nuclear transcription factors, the retinoid receptors, considerable advances have been made in understanding the molecular function of vitamin A. The requirement for vitamin A during early embryogenesis has successfully been examined in the vitamin A–deficient avian embryo during neurulation, when in the vertebrates crucial developmental decisions take place. These studies revealed that retinoic acid is essential during these early stages of embryogenesis for the initiation of organogenesis (i.e., formation of the heart). If retinoic acid is not present at this time, abnormal development ensues, leading to early embryonic death. Though the initial insult of the absence of vitamin A appears to be on the specification of cardiovascular tissues, subsequently all development is adversely affected and the embryo dies. Molecular and functional studies revealed that retinoic acid regulates the expression of the cardiogenic transcription factor GATA-4 and several heart asymmetry genes, which explains why the heart position is random in vitamin A–deficient quail embryos. During the crucial retinoic acid–requiring developmental window, retinoic acid transduces its signals to genes for heart morphogenesis via the receptors RARalpha2, RARgamma, and RXRalpha. Elucidation of the function of vitamin A during early embryonic development may lead to a better understanding of the cardiovascular birth defects prevalent in the Western world.