Experimental Biology and Medicine 229:598-606 (2004)
© 2004 Society for Experimental Biology and Medicine
MINIREVIEW
Vitamin A Requirement for Early Cardiovascular Morphogenesis Specification in the Vertebrate Embryo: Insights from the Avian Embryo
Maija H. Zile1
Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan 48824
1To whom requests for reprints should be addressed at Department of Food Science and Human Nutrition, Michigan State University, 234 G.M. Trout Bldg., East Lansing, MI 48824. E-mail: zile{at}msu.edu
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Abstract
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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 RAR
2, RAR
, and RXR. 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.
Key Words: vitamin A–deficient • quail embryo • retinoic acid • retinoid receptors • cardiovascular development
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Introduction
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It is well-known that vitamin A is an essential nutrient. However, it is only within the past two decades that researchers have begun to decipher the molecular functions of this pleiotropic growth regulator, now viewed as a hormone-like molecule that can alter gene activity. A recent review (1) points out that more than 532 genes have been identified as either direct or indirect targets of the active form of vitamin A; the genes linked to vitamin A are involved in many signaling pathways found in cells at all stages of the life cycle. The vitamin A field is immense; the interested reader is directed to the paper of Balmer and Blomhoff (1) for a list of reviews that cover various specialized areas of vitamin A function. Other recent reviews include overviews of the role of vitamin A in embryonic and fetal development (2, 3), the function of vitamin A in early embryonic development (4, 5), as well as discussions focused on the central nervous system (6–8), and skeletal (9) and pulmonary (10) development. The roles of retinoids in vertebrate heart cushion development, looping, segmentation, chamber maturation, and subsequent later events have also been reviewed (2, 11). The current minireview examines the role of vitamin A during early vertebrate embryonic development and is based on the data obtained with an avian embryo model in which complete vitamin A deficiency is obtained beginning at fertilization, and which thus allows for the examination of the function of retinoic acid during very early development. The emphasis here will be on cardiovascular development, the first morphogenetic event that takes place during vertebrate embryogenesis.
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Function of Vitamin A: Retinoic Acid, Retinoid Receptors, and Gene Regulation
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The need for proper vitamin A nutrition throughout the life cycle is well established (12, 13), but the molecular mechanism(s) of action of this micronutrient are still under investigation. It had been proposed that retinoic acid is the biologically active form of vitamin A at the gene level, but it was the discovery of nuclear receptors for retinoic acid, the RARs, and the retinoid-X-receptors, the RXRs that provided a breakthrough in the understanding how vitamin A–active molecules exert an effect on genes (2, 14, 15). The pleiotropic effects of vitamin A are attributable to a multitude of retinoic acid–linked transcriptional pathways involved in a number of cellular processes (1). Except for its role in vision, these effects of vitamin A are mediated by its physiologically active form, all-trans-retinoic acid (RA) and possibly some of its metabolites, via specific nuclear receptors that are members of the steroid superfamily of ligand-activated transcription factors (reviewed in 2, 14, 16); that is, the retinoic acid receptors RAR, ß, and and the retinoid X receptors RXR, ß, and . Retinoid receptors bind to specific RA responsive elements (RARE) as RAR/ RXR hetrodimers, and their transcriptional effects (activation or repression) depend on the recruitment of co-activators and co-repressors, respectively, in the presence or absence of RA (14, 16, 17). A recent and unexpected finding suggests that retinoic acid is also a high-affinity selective ligand for the orphan peroxisome proliferator-activated receptor ß/
(18).
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Requirement of Vitamin A for Normal Embryonic and Fetal Development
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The requirement of vitamin A for normal embryonic and fetal development is known from many nutritional studies (13, 19). It was recognized already in the 1930s that maternal insufficiency of vitamin A during pregnancy results in fetal death or abnormalities in the offspring that include abnormal heart and central nervous system development (20–22). Both vitamin A deficiency and excess have profound effects on morphogenesis and organogenesis of the vertebrate embryo (reviewed in 4, 5). Studies with exogenously applied retinoids have been used to manipulate and perturb normal embryonic development and have provided evidence that almost every organ or tissue system can be severely affected by retinoic acid if the embryo is treated with it at a crucial time in development (23–28). These studies have provided evidence that retinoic acid via its nuclear receptors can regulate the expression of developmental genes. However, these approaches used concentrations well above endogenous levels and may not reflect the physiological functions(s) of vitamin A in normal development.
A large amount of valuable information regarding the function of vitamin A during embryonic and fetal development has been gathered by the use of transgenic mice with mutations in retinoid receptor genes (2, 9, 14, 29–31), and it has become clear that RAR/RXR heterodimers are essential for most of the events during embryogenesis and fetal development (2, 14). Many of the abnormalities in these mutant mice resemble those observed in fetuses from the vitamin A–deprived animals reported earlier; however, there are defects displayed by these mutants that do not occur in fetuses from nutritionally vitamin A–deprived dams. It has been suggested that unliganded retinoid receptors may also be involved in development (9, 16). Furthermore, elucidation of the function of the recently identified retinoic acid–specific receptor PPARß/ (18) will undoubtedly fill in some gaps regarding the function of retinoic acid during development.
Another important approach to the examination of molecular mechanisms of retinoid action in developmental regulation is the use of in vivo embryo model systems in which the function of vitamin A has been diminished by interfering with vitamin A metabolism during various stages of development. These approaches have included knocking out the genes of the retinoic acid synthesizing enzymes, that is, Raldh2 (32–34) and Raldh3 (35),and the overexpression of the retinoic acid degrading enzyme, Cyp 26 (2, 36). Using nutritional deprivation of vitamin A in a rat model, it is possible to obtain near vitamin A deficiency in the dams and to target embryonal vitamin A insufficiency to distinct gestational windows. These rat embryos exhibit specific cardiac, limb, ocular, and central nervous system abnormalities, some of which have certain features similar to those reported in retinoid receptor knockout mice (4–6, 37–39).
Altogether, though numerous studies have addressed the function of RA in embryonic development, the models used have resulted in diverse phenotypes because of an incomplete inactivation of RA signaling (discussed in 40–43) or, in the case of retinoid receptor knockouts, they do not provide a complete and clear vitamin A deficiency phenotype due to retinoid receptor redundancy (42) and the broad role of the RXRs as co-receptors for other nuclear receptors in nonretinoid signaling pathways (2, 5, 14). A recent comprehensive review of the genetic dissection of retinoid signaling pathways points out the shortcomings of germ-line mutagenesis in addressing the physiological functions of vitamin A and discusses new strategic approaches (16).
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The Vitamin A–Deficient Avian Embryo Model
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The absolute essentiality of vitamin A for early embryogenesis is most clearly demonstrated in the vitamin A–deficient (VAD) avian embryo (44); that is, the quail embryo retinoid ligand knockouts. These completely vitamin A–deficient embryos develop gross abnormalities in the cardiovascular and central nervous systems and trunk, and die by Day 3.5–4 of embryonic life (4–7, 45–47). These embryos are devoid of any form of vitamin A or its precursors from the beginning of fertilization. This complete VAD phenotype, due solely to the absence of RA, has not been reported in other model systems, because in receptor knockouts there are complications introduced by retinoid receptor redundancy or side effects due to RXR functions in other growth regulatory pathways or there is residual vitamin A activity in other nutritional models (see above). The Raldh2 knockout phenotype (32) most closely approaches the avian VAD phenotype, but a complete VAD phenotype was not produced, likely due to the presence of other RA generating systems (35, 48, 49). An illustration of the VAD phenotype of the avian model discussed here is shown in Figure 1
. Importantly, the VAD embryo can be "rescued" and the normal developmental program restored by the administration of the physiological ligand for RARs, all-trans-retinoic acid, or its precursor, retinol, prior to or during a crucial, retinoic acid–requiring time in neurulation when important developmental events are specified.
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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.
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Clearly, the mechanisms involved in embryonic cardiovascular morphogenesis are complex as they are coordinated by different processes, several of which appear to be adversely affected by the lack of vitamin A. With the VAD avian (quail) model, it is possible to examine morphological, anatomical, and molecular biology aspects that are attributable solely to vitamin A. The ability to rescue the VAD embryo at a precise time during development makes this model a powerful tool for the elucidation of the physiological functions of vitamin A during early development and makes it possible to answer fundamental questions about early heart development that could not be answered otherwise.
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Embryo Survival Depends on Retinoic Acid Signaling Very Early in Development
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Crucial developmental decisions in the vertebrates take place during the neurulation stage, which is inaccessible to in vivo manipulation in mammals but easily accessible in the avian embryo. Using the VAD quail embryo model, several important observations were made regarding the function of vitamin A in early embryonic development in general and in heart development in particular. There is a developmental time window at the Hamburger & Hamilton (50) stage HH8, during the 4–5 somite stage (ss) of neurulation, when crucial RA-dependent decisions are made about subsequent major developmental events; this is also the developmental time when RA signaling is first required in the avian embryo (5, 45–47). This time coincides with that of embryonic cell terminal differentiation; that is, the process by which the embryonic cells attain biochemical and functional identity and enter a state of "determination" in which this identity cannot be changed. This concept has been verified in the VAD embryo by not being able to "rescue" the VAD embryo genotype and phenotype if vitamin A is provided after this crucial stage (5, 45, 46). Although RA, retinoic acid–generating systems (51–53), as well as retinoid receptor gene transcripts (43, 53) are already present in the vertebrate embryo prior to this crucial window, it is not until the time of initiation of RA requirement (also the initiation of organogenesis, i.e., the formation of the heart) that the embryo first requires vitamin A for implementing a multitude of crucial, life-sustaining developmental decisions (4, 5, 43, 45, 47, 54). It appears that the retinoic acid receptors RAR2 and RAR, together with RXR, are the essential and specific RARs required to transduce the RA signals at the 4–5 ss for avian embryonic development and survival (54). If RA is not available to the avian embryo at this time, the morphogenesis of the cardiovascular system is impaired, normal development ceases, and the avian embryo dies at approximately 3.5 days of embryonic life as the result of multiple gross abnormalities that include retarded growth, abnormalities in the central nervous system and the skeletal structure, the lack of a circulatory system, an abnormal, noncompartmentalized and dilated heart lacking an inflow tract and oriented randomly; that is, the entire embryonic developmental process is disturbed and subsequently arrested if RA signaling is absent at this step. It remains to be investigated which developmental aspects are directly affected by the lack of RA signaling at the early crucial time for RA requirement and which are the consequences of earlier patterning defects. It is very important to note that the early developmental pathways are comparable across vertebrates (55, 56), thus the findings are applicable to the role of vitamin A in the early human embryo.
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Vertebrate Cardiovascular Development
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Using the avian VAD embryo model, it has been possible to deduce that the initial and predominant phenotype of the vitamin A–deficient vertebrate embryo (i.e., a grossly abnormal heart and an absence of circulation) is the result of a failure of normal cardiovascular development to take place (57–59). Because the heart is the first organ formed in the embryo and vasculature is the first system intimately linked to heart morphogenesis, essential for providing nutrients to the developing embryo, it is inevitable that the failure of these processes to take place normally results in early embryonic death, which is the case of the VAD avian embryo.
Here we will briefly outline the basic morphological events that encompass the early stages of avian embryogenesis during which, we believe, vitamin A is crucially involved in the regulation of normal cardiovascular development. The early development of the avian heart has been summarized by Hamburger and Hamilton (50), followed by excellent subsequent reviews of the expanding field (60–64). The current perspectives on embryonic vascular development have been reviewed by Drake (65). Two basic types of processes are involved in cardiovascular development: those that drive morphological development (e.g., migration, proliferation, and apoptosis) and those necessary for functional development, including the specification, differentiation, and determination of cardiogenic tissues (66). The cells programmed to form the heart arise in the epiblast at Hamburger and Hamilton (HH) stage 3 embryo (primitive streak stage in quail embryo; approximately Day 15 of the human embryo), from where they migrate, then assemble in the heart fields and subsequently migrate to their destined placement sites as embryonic development proceeds (62). After aligning into a cardiogenic crescent (~Day 20 in the human embryo), the precardiac cells differentiate and assemble as the bilateral heart tubes (24, 67). At this time, vasculogenesis is also taking place (65) as the formation of the vasculature is tightly correlated with heart development (68, 69). The extraembryonal vascular networks converge into vitelline veins at the posterior region of the developing heart, link with the vascular endocardium and form the cardiac inflow tract; this area is also called the sinus venosus (69). Next, a single heart tube, linked to the extraembryonal circulation via the inflow tract, is formed in the avian embryo (24, 67), approximately at 22 days of human embryonic development. The heart orientation to the right is first observed at HH10; at this stage, the heart also begins to contract (60). The subsequent stages involve a series of complex steps during which the tubular heart is transformed into a multichambered organ (60).
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Vitamin A and Heart Morphogenesis
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It is well established that maternal insufficiency of vitamin A during pregnancy results in developmental abnormalities in the offspring, including aberrant heart development that may lead to death (20–22). Regulation of retinoid signaling is a conserved component of normal cardiogenesis, as evidenced by the severe cardiac abnormalities seen when excess vitamin A is present during pregnancy as well as when administered directly to embryos (23, 24, 70–72). Similarly, the phenotypes of mice with targeted disruption in retinoid receptor genes (73–75) are consistent with a crucial role for vitamin A in heart development. Many of these mutant mice have defective cardiac morphogenesis (73–76), similar to the cardiovascular abnormalities caused by vitamin A insufficiency. Receptor knockout studies suggest that different receptors perform different functions within different domains of the developing heart (77). However, the underlying cellular and molecular events of early embryonic development that are regulated by endogenous vitamin A–active molecules have not been elucidated.
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Molecular Aspects of Vitamin A–Regulated Cardiovascular Development
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There are no master regulators in heart development, instead many signaling pathways participate in important and complex interactions to form a heart from the embryonic mesoderm. Among the early signaling molecules regulating cardiac progenitor differentiation are the transforming growth factor beta (TGFß) family of growth factors, including activins A and B, TGFß2 and ß3, and BMP2 and 4 (reviewed in 78–80). This family of genes is also involved in cardiac left/right determination and in precardiac cell differentiation into cardiomyocyte lineage. Members of the TGFß family of cytokines have been implicated in heart (81, 82) and vascular (83–85) development. The primary receptor for TGFß, the transforming growth factor-ß receptor type II (TBRII), is present in endothelial cells and marks the extraembryonal vascular networks in quail and chicken (83). There is strong evidence for the involvement of the TGFß in cardiac morphogenesis (81, 83, 85, 86). This is supported by TGFß2 knockout mice, which have multiple developmental defects, including heart defects that share abnormal features with those reported in the offspring of vitamin A–deficient mice (22) and with the developmental defects observed in retinoic acid receptor knockouts (87, 88). It is well-known that in many cells, RA regulates TGFß signaling (86, 89–94), but the TGFß-RA relationship is not understood. The promoters of the TGFß genes do not contain RARE, indicating that an indirect method of regulation is involved (86). A recent study finds TGFß2 increased in the RXR knockout mice embryos, leading to increased apoptosis in the heart outflow tract (95). A potential involvement of retinoid-regulated TGFß function in early embryogenesis has also been suggested by the observation of altered TGFß expression in the early VAD quail embryo (96). It has been suggested that members of the TGFß family are downstream effectors in a RA signaling pathway (11), but the link to cardiovascular development remains to be elucidated.
Several transcription factors have been linked to the process of cardiac commitment and differentiation and include the homeobox genes Nkx2.5, Hoxa genes, Msx-1, and the GATA-4/5/6 family of transcription factors (reviewed in 97, 98). Nkx2.5 gene knockouts result in abnormal heart development and the absence of heart looping (99), similar to some of the defects observed in the VAD quail embryo. However, the expression of this gene was not altered in the VAD quail embryo (46). The GATA genes are implicated in the regulation of several processes linked to the development of the cardiovascular system, including cardiogenesis, erythropoiesis, and, indirectly, vasculogenesis (78, 100). GATA-4 transcripts are particularly high in the posterior heart tube (101), suggesting a role for this transcription factor in cardiac inflow tract formation. This observation led to an examination of the expression of GATA-4 in the VAD quail embryo, which does not form the inflow tract, the complex structure that links the embryonic heart to its extraembryonal circulation; it is built from vascular, endocardial, and myocardial precursors. It was found that GATA-4 expression in the VAD quail embryo is severely diminished in the cardiac inflow tract–forming area and that this RA-regulated GATA-4 signaling pathway takes place within the crucial RA-requiring developmental window (46). Importantly, an examination of the expression of cardiac muscle–specific genes revealed that cardiomyocyte differentiation is not regulated by RA signaling pathways in the in ovo quail embryo (46), although different results are obtained with cells in culture (102). Though the mechanisms involved are not yet clarified, it is interesting to note that in the avian embryo, vitamin A deficiency causes an inappropriate increase in apoptosis in the posterior heart-forming regions and in the foregut (103) and also in the central nervous system (104, 105). Furthermore, in the VAD quail embryo, enhanced apoptosis was observed in the primitive erythroid cells during hematopoiesis, a process regulated by retinoic acid via GATA factors (106).
The retinoid receptors RARs and RXRs are also important transcription factors linked to heart development, as convincingly demonstrated by the use of knockout approaches, that have resulted in a wide spectrum of heart abnormalities (reviewed in 2, 11). Recent studies (43) demonstrate that all retinoid receptors are expressed in the heart-forming areas of the early quail embryo; it was also established that an adequate expression of RAR2 and RARß2 depends on the presence of retinoic acid and that the expression of RAR2 is required for the induction of RARß2 (43). Though RAR2 and RAR are the essential and specific RARs required to transduce the RA signal during the 4–5 ss for normal avian embryonic development and survival, additionally, they have specific functions in heart development; that is, RAR2 has a distinct role in cardiac inflow tract formation, whereas RAR regulates cardiac L/R asymmetry and looping (54). This, for the first time, identifies distinct and nonredundant roles for individual retinoic acid receptors in heart morphogenesis.
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Heart Asymmetry, Looping, and Vitamin A
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An essential aspect of cardiac morphogenesis is the establishment of proper heart sidedness (i.e., asymmetry). The asymmetry pathway is set up early in embryogenesis and is tightly regulated by a balance between transient stimulatory and inhibitory stage-specific signals involving many genes (107). Manipulations of embryos in culture and in vivo, using exogenous and excess retinoic acid and other nonphysiological approaches, have implied a direct role for vitamin A in the regulation of vertebrate heart asymmetry genes (24). Early studies in our laboratory revealed that in many VAD quail embryos, the heart was on the wrong side (59); these observations led to an examination of the role of vitamin A in heart asymmetry. It was established that RA regulates the expressions of the heart asymmetry genes nodal, snail, and Pitx2, which are involved in the final stages of heart left/right determination, whereas the expression of the very early cardiac asymmetry genes is not altered by the absence of vitamin A. The asymmetry-associated RA-regulated molecular events take place within the crucial RA-requiring developmental window (5, 47). The important conclusion from these studies is that under physiological conditions, retinoic acid does not regulate the left/right specific sidedness assignments for expression of genes on the early vertebrate cardiac asymmetry pathway, but that it is required later, during neurulation, for the maintenance of adequate levels of expression (i.e., a sufficient level of signaling molecules) of the late asymmetry genes as well as for the development of the posterior heart tube and a loopable heart. In the absence of vitamin A, the cardiogenic cells lack instruction for direction and their migration to either left or right of the midline is random. Indeed, in the VAD embryos the orientation of the heart is random (47). After establishing asymmetry, the heart tube begins to form an S-shaped structure (looping), which is a prerequisite for the formation of heart chambers. Recent findings suggest that retinoic acid regulates heart asymmetry and looping via a RAR signaling pathway (54).
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Function of Vitamin A in Forming Embryonic Vasculature
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In the VAD quail embryo, initially the embryonal and extraembryonal vascular systems appear to develop normally; however, subsequently, the vascular networks are not maintained, the vitelline veins do not form, and the endocardial tubes close, thus there is no cardiac inflow tract (5). Unpublished studies in our laboratory suggest that the abnormal vascular morphogenesis in the VAD embryo is correlated to diminished vascularization; this defect can be rescued by the administration of vitamin A to the VAD embryo prior to or during the early crucial time window. It might be of interest to examine if the expression of the extracellular matrix protein fibronectin is altered by vitamin A status, as treatment of embryos with an antibody to fibronectin disrupts cell migration and causes an abnormal heart development (108, 109); similar effects are obtained by treating embryos with exogenous retinoic acid (24). Furthermore, fibronectin knockout mice have an abnormal but beating heart and defects in vasculogenesis (110).
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Conclusions and Perspectives
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Early embryonic heart development across the vertebrates is comparable (55, 56), thus many analogies can be drawn from such studies for an application to the human. This is particularly relevant because congenital heart defects in the Western industrialized world are as high at 12 per 1000 live births and represent about 10% of all congenital malformations (111–114); pediatric cardiovascular abnormalities account for 8% of all deaths during the first year of life. In the United States, 3% of all children born have a major malformation at birth, and 70% of these are of unknown etiology. Growth retardation and prenatal or early postnatal death also occur at a high ratio in our population, but information is not available as to their possible causes. At this time, there is no understanding of the molecular basis of birth defects linked to heart—the research area reviewed here. More and more clinical data, however, confirm that it is important to look at nutritional and dietary contributions to birth defects. Though a genetic predisposition to congenital heart disease is likely present in certain cases, it is also likely that a second or third insult such as vitamin A insufficiency or a disturbance in vitamin A function during embryogenesis (i.e., during pregnancy) contributes to the cardiovascular defects observed clinically. The crucial vitamin A–requiring developmental events coincide with the first 2–3 weeks of human pregnancy; they may be severely compromised if maternal vitamin A intake is marginal or if there is an interference with vitamin A function during pregnancy. The high incidence of vitamin A deficiency in developing countries may account for the increased incidence of heart malformations in these populations (115).
The observations presented here strongly point to a crucial role of vitamin A during a relatively limited time window in early embryonic development, when the presence of the vitamin A active form, retinoic acid, is absolutely essential for normal cardiovascular development to take place and, subsequently, for embryo to survive. It is during this time when the vitamin A active form is first required for embryogenesis, either directly or indirectly initiating early developmental gene pathways that affect many aspects of the subsequent embryogenesis. Regardless if one looks with the eyes of an astronomer, physicist, theologian, biologist, or embryologist—it is not easy to decide when something begins. It is the same regarding the question of when does vitamin A requirement begin in the vertebrate. Examining vitamin A function in the early embryo using the avian vitamin A knockout model, we have deduced that the very early processes of life, such as building the body plan during gastrulation, can proceed normally without vitamin A, but that at the stage when the embryo has a heavy demand for those specialized functions that are most effectively carried out by vitamin A, that this micronutrient becomes absolutely essential for embryonic life to continue. The well-known property of retinoic acid as a differentiation agent may well be at the core of the signaling events during the crucial early developmental window when the embryo depends on vitamin A for its ultimate survival.
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Footnotes
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This work was supported in part by the National Institutes of Health Grant 5R01 HL61982 03, the U.S. Department of Agriculture Grant 00-35200-9062, and the Michigan Agricultural Experiment Station.
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Abstract
Introduction
