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Retinoic acid (RA) is a terpenoid that is synthesized from vitamin A/retinol (ROL) and binds to the nuclear receptors retinoic acid receptor (RAR)/retinoid X receptor (RXR) to control multiple developmental processes in vertebrates. The available clinical and experimental data provide uncontested evidence for the pleiotropic roles of RA signaling in development of multiple embryonic structures and organs such eyes, central nervous system, gonads, lungs and heart. The development of any of these above-mentioned embryonic organ systems can be effectively utilized to showcase the many strategies utilized by RA signaling. However, it is very likely that the strategies employed to transfer RA signals during cardiac development comprise the majority of the relevant and sophisticated ways through which retinoid signals can be conveyed in a complex biological system. Here, we provide the reader with arguments indicating that RA signaling is exquisitely regulated according to specific phases of cardiac development and that RA signaling itself is one of the major regulators of the timing of cardiac morphogenesis and differentiation. We will focus on the role of signaling by RA receptors (RARs) in early phases of heart development. This article is part of a Special Issue entitled: Nuclear receptors in animal development.

We discuss coronary ontogeny and function in an evolutionary framework. Coronary morphogenesis is old, appearing at the level of the first jawed vertebrates. After its origins, the presence or absence of coronaries seems to be dictated more in response to physical activity than due to phylogenetic origin. The major coronary vessels derive from the proepicardium, which is a cellular progenitor of the epicardium, coronary endothelium, and coronary smooth muscle cells. Here we review the basic notion that coronary development is a highly organized process, in which coronary endothelial differentiation and tubular morphogenesis precedes coronary smooth muscle cell differentiation and incorporation into true coronary vessels. Some years ago, we showed that these complex steps are orchestrated by retinoic acid and the vascular endothelial growth factor. We also examine new views on the origins of coronary vessels (i.e., the sinus venosus) and explore the potential of the epicardium in coronary and cardiac regeneration.

The teratogenic mechanisms triggered by ZIKV are still obscure due to the lack of a suitable animal model. Here we present a mouse model of developmental disruption induced by ZIKV hematogenic infection. The model utilizes immunocompetent animals from wild-type FVB/NJ and C57BL/6J strains, providing a better analogy to the human condition than approaches involving immunodeficient, genetically modified animals, or direct ZIKV injection into the brain. When injected via the jugular vein into the blood of pregnant females harboring conceptuses from early gastrulation to organogenesis stages, akin to the human second and fifth week of pregnancy, ZIKV infects maternal tissues, placentas and embryos/fetuses. Early exposure to ZIKV at developmental day 5 (second week in humans) produced complex manifestations of anterior and posterior dysraphia and hydrocephalus, as well as severe malformations and delayed development in 10.5 days post-coitum (dpc) embryos. Exposure to the virus at 7.5–9.5 dpc induces intra-amniotic hemorrhage, widespread edema, and vascular rarefaction, often prominent in the cephalic region. At these stages, most affected embryos/fetuses displayed gross malformations and/or intrauterine growth restriction (IUGR), rather than isolated microcephaly. Disrupted conceptuses failed to achieve normal developmental landmarks and died in utero. Importantly, this is the only model so far to display dysraphia and hydrocephalus, the harbinger of microcephaly in humans, as well as arthrogryposis, a set of abnormal joint postures observed in the human setting. Late exposure to ZIKV at 12.5 dpc failed to produce noticeable malformations. We have thus characterized a developmental window of opportunity for ZIKV-induced teratogenesis encompassing early gastrulation, neurulation and early organogenesis stages. This should not, however, be interpreted as evidence for any safe developmental windows for ZIKV exposure. Late developmental abnormalities correlated with damage to the placenta, particularly to the labyrinthine layer, suggesting that circulatory changes are integral to the altered phenotypes., Author summary Previously thought to produce a harmless bout of fever associated with skin rash and muscle, or joint pain, the Zika virus (ZIKV) is an important cause of morbidity/mortality to human embryos/fetuses. Different from other models, here we report data from wild-type immunocompetent mice, rather than transgenic animals with suppressed immune responses. We found that intravascular ZIKV produced infection of maternal tissues, placentas and conceptuses, but that embryos/fetuses were comparatively much more affected than pregnant females, which seemed to tolerate well the viral challenge with no signs of encephalopathy. Importantly, 10.5 days post-coitum (dpc) embryos exposed to ZIKV at embryonic day 5 (second week in humans) displayed dysraphia, which is a regional failure of neural tube closure, and hydrocephalus, which is a symptom recently shown to precede microcephaly in humans. Characteristic phenotypes in more developed embryos/fetuses included abnormal articular postures analogous to arthrogryposis, which are typical human congenital contractures, gross and generalized malformations and intra uterine growth restriction (IUGR), rather than isolated microcephaly. Some developmental abnormalities and IUGR correlated with placental damage, suggesting that loss of placental function may play an important role in the disease. We believe our model is an asset in the search for useful concepts and prospective therapies for ZIKV because it better reproduces the human condition.