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Articles

Function of Vitamin A in Vertebrate Embryonic Development^{1 ,2}

Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI 48824

	ABSTRACT

TOP ABSTRACT INTRODUCTION Retinoic Acid, a Critical... Model Systems for the... Heart and Blood Vessel... The Central Nervous System. Development of Limbs,... Summary and Perspectives. REFERENCES

 
Advances in molecular biology and retinoic acid receptor research have significantly contributed to the understanding of the role of vitamin A during vertebrate development. Examination of the function of this vitamin during very early developmental stages using the completely vitamin A–depleted avian embryo has revealed that the vitamin A requirement begins at the time of formation of the primitive heart, circulation and specification of hindbrain. The lack of vitamin A at this critical time results in gross abnormalities and early embryonic death. In rodent models, vitamin A deficiency can be targeted to later gestational windows and documents the need for vitamin A for more advanced stages of development. Major target tissues of vitamin A deficiency include the heart, central nervous system and structures derived from it, the circulatory, urogenital and respiratory systems, and the development of skull, skeleton and limbs. These abnormalities are also evident in mice mutants from retinoid receptor knockouts; they have revealed both morphological and molecular aspects of vitamin A function during development. Retinoic acid receptors (RAR) in partnership with retinoid X receptor (RXR) appear to be the important retinoid receptor transcription factors regulating vitamin A function at the gene level during development via the physiologic ligand all-trans-retinoic acid. Homeostasis of retinoic acid is maintained by developmentally regulated vitamin A metabolism enzyme systems. Inadequate vitamin A nutrition during early pregnancy may account for some pediatric congenital abnormalities.

KEY WORDS: • vitamin A • avian development • retinoic acid

	INTRODUCTION

TOP ABSTRACT INTRODUCTION Retinoic Acid, a Critical... Model Systems for the... Heart and Blood Vessel... The Central Nervous System. Development of Limbs,... Summary and Perspectives. REFERENCES

 
Theessentiality of vitamin A nutrition throughout the life cycle has been well established. Most importantly, the requirement for vitamin A begins with embryonic life as noted by early nutritionists who reported that maternal insufficiency of vitamin A during pregnancy results in fetal death or congenital abnormalities in the offspring (1 2 3 4) . During the last decade, there has been great interest in the area of vitamin A function in development as reflected in a number of recent detailed reviews on the subject (4 5 6 7 8) .

	Retinoic Acid, a Critical Signaling Molecule in the Vertebrate Embryo.

TOP ABSTRACT INTRODUCTION Retinoic Acid, a Critical... Model Systems for the... Heart and Blood Vessel... The Central Nervous System. Development of Limbs,... Summary and Perspectives. REFERENCES

 
The elucidation of how vitamin A exerts its pleiotropic effects has become a molecular biology–driven endeavor for many nutritionists since the discovery and realization that the biological effects of vitamin A, except for its role in vision, are mediated by its active form, all-trans-retinoic acid via specific nuclear receptors that are members of the steroid superfamily of ligand-activated transcription factors (4 ,8 9 10) , i.e., the retinoic acid receptors (RAR)³ , ß and that are activated by retinoic acid (RA), and the retinoid X receptors (RXR) , ß and that are obligatory partners for the RAR. The RAR-RXR heterodimers are the functional units in transducing the retinoid signal at the gene level. The pleiotropic effects of vitamin A are explained by the discovery that many of the RA target genes are genes involved in diverse biological processes (4 ,8 9 10) . Redundancy of retinoid receptors, evidenced in studies with receptor gene knockouts (4) , attests to the paramount importance of vitamin A in development. During the course of normal embryonic development, distinct developmental events are regulated by the presence of the vitamin A active form, RA. The function of vitamin A is inseparable from its metabolism because the biogeneration of RA in the embryo is the first developmental step in the initiation of RA-regulated signaling pathways and must be linked to regulated metabolic systems for the inactivation of unused RA. All of the physiologically important vitamin A metabolites and enzyme systems that regulate vitamin A metabolism have been demonstrated in embryos (3 4 5 6 7 8 ,11 12 13 14 15) .

	Model Systems for the Study of Vitamin A Function in Embryonic Development.

TOP ABSTRACT INTRODUCTION Retinoic Acid, a Critical... Model Systems for the... Heart and Blood Vessel... The Central Nervous System. Development of Limbs,... Summary and Perspectives. REFERENCES

 
Vitamin A deficiency and excess have profound effects on the development of the vertebrate embryo (3 4 5 6 7 8) . Almost every organ or tissue can be affected by RA if the embryo is treated with it at a critical time in development (16) . A vast amount of information has been gathered on vitamin A function at the molecular level from cell culture (4 ,10 ,17) and from in vivo studies by perturbing normal embryonic development with exogenous retinoids (4 5 6 7 8 ,10) . The abnormalities observed in these studies, when viewed together with similar abnormalities reported for the vitamin A–deficient (VAD) embryo and fetus, identify common development pathways that are severely disrupted by an imbalance in vitamin A status. The function of vitamin A in development has been addressed recently by the use of transgenic mice with changes in retinoid receptor gene structure (4 ,9 ,18 19 20) . Many of the abnormalities in these mutant mice resemble those observed in fetuses from the VAD animals reported earlier. These studies have provided valuable insights into the pleiotropic effects of vitamin A and have demonstrated the critical role of retinoid receptors in vertebrate ontogenesis. The interpretation of the data has been complicated by retinoid receptor redundancy and by the broad role of the RXR as coreceptors for other nuclear receptors (4 ,9) .

An 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 or completely eliminated by removing the vitamin. The absolute essentiality of vitamin A for embryogenesis is most clearly demonstrated in the VAD avian embryo, i.e., the quail embryo retinoid ligand knockouts. The completely VAD embryos develop gross abnormalities in the cardiovascular and central nervous systems and trunk and die by d 4 of embryonic life (3 ,4 ,6 ,7 ,21 22 23) . Importantly, the VAD embryo can be "rescued" and normal development restored by administration of the physiologic ligand for RAR, all-trans-retinoic acid, or its precursor, retinol. Bioactive retinoids must be administered to these embryos during early development so as to be present during the critical window of time in which important developmental events are specified, i.e., the formation of heart, cardiovascular system, hindbrain, foregut and probably other events (21 ,23) . With this model, it is possible to examine morphological, anatomical and molecular biology aspects during development that are solely attributable to vitamin A. The ability to rescue the VAD embryo at a precise time during development makes the avian retinoid ligand knockout model a powerful tool for the elucidation of vitamin A function during early development.

Using rats as a mammalian model, it is possible to obtain near vitamin A deficiency in the dams and to target embryonal vitamin A insufficiency to distinct gestational windows (3 ,4 ,6 ,7 ,24 25 26) . These rat embryos exhibit specific cardiac, limb, ocular and central nervous system (CNS) abnormalities, some of which have certain features similar to those reported in retinoid receptor knockout mice (25) . Abnormalities in hindbrain development of the rat embryos (26) are similar to those reported in VAD quail embryos (7 ,27) and suggest that even partial vitamin A deficiency affects the sensitive developing CNS. These studies have also revealed the importance of vitamin A in fetal lung and kidney development (24 ,28 ,29) .

Another in vivo approach to eliminate vitamin A–active forms is to block RA with an anti-RA antibody (30) or to inactivate the RA generation pathways (4 ,7) . Knockout mice embryos of the RA synthesizing enzyme RALDH2 (11) have many abnormalities similar to those of the VAD quail embryo, but complete vitamin A deficiency was not obtained, probably due to the presence of other RA-generating systems. Partial depletion of RA may also be achieved by an overexpression of CYP26, an enzyme that degrades RA (4 ,13) .

	Heart and Blood Vessel Development.

TOP ABSTRACT INTRODUCTION Retinoic Acid, a Critical... Model Systems for the... Heart and Blood Vessel... The Central Nervous System. Development of Limbs,... Summary and Perspectives. REFERENCES

 
A great deal of information on the effects of retinoids on heart development has been gathered from ectopic application of excess retinoids to embryos (6 ,31 ,32) but physiologically more relevant are the experimental approaches that diminish or eliminate vitamin A function. Maternal insufficiency of vitamin A during pregnancy results in fetal death or severe abnormalities in the offspring, including abnormal heart development; many of the heart defects have been recapitulated in fetuses generated from various combinations of retinoid receptor knockouts. Heart abnormalities obtained include a thin-walled dilated heart cavity, abnormalities in ventricular chambers and defects in the outflow tract (3 ,4 ,6 ,18 19 20 ,22 ,25 ,31) . Important information has also been obtained by molecular analysis (9 ,18 19 20) , but the primary retinoid targets have not been identified. The phenotypes obtained may reflect secondary lesions and abnormalities due to RXR functions with other nuclear receptors (4 ,9) . In contrast, the quail embryo retinoid ligand knockout model allows an analysis of developmental regulation solely attributable to vitamin A and reveals the full function of this vitamin. The model has an advantage for studies of vitamin A function during early precardiac and subsequent heart-forming stages by "rescue" manipulations to restore normal gene expression and cardiogenesis. The VAD cardiac phenotype in this avian model is highly reproducible and, together with molecular analysis, allows us to draw certain conclusions about the initial cardiogenic events regulated by vitamin A (3 ,6 ,21 22 23) . The developing heart is a grossly abnormal, thin-walled, dilated and distended structure, without chambers, but it contracts until the embryo dies. This is not surprising because the expression of early cardiogenic genes that regulate heart precursor cell differentiation into cardiomyocytes is not affected by the lack of vitamin A (22) . In contrast, exogenous treatments with RA induce differentiation of precursor cells into cardiomyocytes (31) .

The concept of a specific retinoid function in axial specification has a long history, originating with the identification of RAR responsive elements in some of the evolutionarily conserved axial patterning genes (33) . It has been perpetuated by results from numerous studies in which exogenous RA applied to embryos of various species at various stages of development affects the specification of body axes, heart asymmetry and limb patterning (5 ,8 ,31 32 33) . These studies suggested a specific role for RA in heart asymmetry determination (23 ,31 ,32) . However, recent evidence points to vitamin A having a general rather than a specific role, i.e., it appears that vitamin A is required to provide a proper environment for the expression of adequate levels of heart asymmetry genes (23) . This concept is supported by evidence from the literature that the generation and distribution of RA in the embryo as well as the expression patterns of vitamin A metabolism enzymes and retinoid receptors are symmetric (7 ,11 12 13 14 ,21) .

A major developmental defect that may be linked directly to the early embryolethality of the VAD quail embryo is the absence of a cardiac inflow tract (3 ,6 ,22) , i.e., the VAD heart has no opening at its caudal end where the extraembryonal blood vessels converge into vitelline veins to deliver blood to the embryonic heart for distribution to the embryo. This defect has not been reported in any of the mammalian in vivo models addressing vitamin A function during embryogenesis. The formation of the cardiac inflow tract may be linked to the expression of the retinoid-regulated cardiac transcription factor GATA-4 in the posterior heart–forming area where this gene is involved in a BMP2 pathway that specifies the endodermal structures of the heart and the underlying foregut primordia, and where apoptosis is observed in the VAD embryo (34) . In these embryos, the extraembryonal vascular networks are sparse and fail to converge at the level of the cardiac inflow tract (35 ; Fig. 1 ). Defects in vitelline vessel formation have also been observed in cultured mouse embryos when the transfer of retinol from the yolk-sac to the embryo is prevented (36) . Anomalies in vasculogenesis have not been reported in retinoid receptor knockout mice, but may have contributed to embryolethality.

View larger version (209K): [in this window] [in a new window]   Figure 1. Vascular development in the 36–38 h normal and vitamin A–deficient (VAD) quail embryo. In the normal embryo, well-formed vascular networks (arrowhead) converge into vitelline veins at the cardiac inflow tract (black arrows); the VAD embryo has sparse, disorganized vascular networks and poorly developed vitelline veins. Heart (large arrows) has begun to loop in the normal embryo but is abnormal in the VAD embryo. Note the distorted head and short body in the VAD embryo. All views are ventral

	The Central Nervous System.

TOP ABSTRACT INTRODUCTION Retinoic Acid, a Critical... Model Systems for the... Heart and Blood Vessel... The Central Nervous System. Development of Limbs,... Summary and Perspectives. REFERENCES

	Development of Limbs, Respiratory System and Other Systems.

TOP ABSTRACT INTRODUCTION Retinoic Acid, a Critical... Model Systems for the... Heart and Blood Vessel... The Central Nervous System. Development of Limbs,... Summary and Perspectives. REFERENCES

 
Retinoids have long been linked to vertebrate limb morphogenesis, mainly as the result of studies involving induction of genes and morphologic anomalies with exogenous retinoids. Results from these numerous studies have been summarized in several recent publications which detail the morphology and the genetic pathways and propose mechanisms for retinoid involvement (4 ,5 ,8 ,40) . Recent examination of limb patterning in a physiologically relevant model suggests that studies with ectopic retinoids may not accurately reflect the function of vitamin A in normal limb development (40 ,41) . The completely VAD quail embryo does not live long enough to develop limbs, but in contrast to earlier notions, the initiation of limb bud development occurs in the absence of vitamin A. Analysis of the expression of developmental genes in these limb buds has revealed an important role for vitamin A in patterning the dorsoventral axis (40) . It is not clear how the abnormal limb patterning pathways in VAD avian limb buds relate to the limb malformations observed in certain retinoid receptor mutants (4) ; the malformed limbs may be the result of marginal retinoid activity during a later period in development. Interestingly, mice knockouts of the RALDH2 gene, an enzyme involved in the generation of RA, do not appear to have limb buds (11) , suggesting species differences.

Using partially vitamin A–depleted rodent models in which the fetuses survive longer and later gestational windows can be examined, it was demonstrated that vitamin A is specifically required during midgestation for fetal lung development and neonatal survival (24 ,42) . Abnormal cell differentiation and diminished expression of elastin gene and a growth-arrest gene were associated with abnormal lung morphology (42) , also seen in mice with deletions in RAR genes (29) . Compound mutants of RAR also exhibit congenital respiratory tract abnormalities (4 ,19) . The importance of adequate maternal/fetal vitamin A nutrition in prevention of neonatal lung injury has been demonstrated clinically and in animal models (28) . Similarly, renal development is affected by retinoids (43) , also noted in the RALDH2 knockout mice (11) ; congenital malformations in the urogenital system are seen in fetuses of RAR compound mutant mice (4) .

	Summary and Perspectives.

TOP ABSTRACT INTRODUCTION Retinoic Acid, a Critical... Model Systems for the... Heart and Blood Vessel... The Central Nervous System. Development of Limbs,... Summary and Perspectives. REFERENCES

 
Early animal studies on vitamin A requirement during pregnancy as well as more recent rodent depletion models have provided important information regarding the role of this vitamin during specific gestational windows. However, complete vitamin A deficiency is necessary to reveal the full function of vitamin A during early development as best illustrated in the avian embryo vitamin A knockout model. Results from these experiments suggest that the requirement for vitamin A activity in the embryo begins at the time of first organ system initiation, not earlier. This hypothesis is in agreement with the conclusions reached by Durston et al (33) who noted that the gain and loss of function experiments with retinoid receptors do not demonstrate significant changes during early embryogenesis and thus challenge the existing hypothesis that RA signaling is essential at the time of embryonal cell organization and initial axial patterning. Results from the avian studies provide strong evidence that the absolute vitamin A requirement begins at the time of formation of the primordial heart tube, the linking of the extraembryonal vascular system to the developing heart and the specification of hindbrain. These critical events in the avian embryo take place at the same developmental time and correlate to first 2–3 wk of human pregnancy, emphasizing the importance of adequate vitamin A nutrition during initial stages of pregnancy. If vitamin A is completely lacking during this critical time, development takes place along a default pathway, resulting in gross abnormalities and early embryolethality. In marginally vitamin A–deprived rat embryos or with some retinoid receptor knockouts, the requirement for vitamin A can be demonstrated for later, more advanced developmental events. Certain retinoid receptor knockouts recapitulate many of the vitamin A deficiency symptoms, but do not provide a clear vitamin A deficiency phenotype because of receptor redundancy and the pleiotropic effects from RXR acting as partners with multiple nuclear receptors (4 ,9 ,18 ,31) . Altogether, all observations support the requirement for vitamin A during multiple stages of development for numerous tissues and organs. Consistent with the many roles of vitamin A in development, retinoid receptors are widely expressed in the vertebrate embryo (4 ,12 ,31) . Retinoid receptor knockout studies have revealed that for developmental function, there is very little redundancy among the RAR subtypes, and that RXR is the major partner for the RAR in RA signaling (4) . The RAR-RXR heterodimer is most likely activated by the RAR ligand, all-trans-retinoic acid, with RXR acting as enhancers in RA signal transduction (9) . The present data suggest that during embryogenesis, all-trans-retinoic acid is the sole active form for all retinoid functions involving retinoid receptors. Vitamin A function during embryogenesis is locally regulated by a spatiotemporal developmental expression of RA- generating and -inactivating enzymes and further fine-tuned through a diversity of receptors and their isoform combinations. A number of genes are known to have RAR responsive elements (4 ,8 ,10) , but it is not known which genes are causally and directly linked to the VAD phenotype. At this time, no immediate RA target genes have been identified for any developmental event, and no single protein, other than the RAR and RXR proteins, is known to be linked directly to vitamin A function. RA effector genes may be important genes involved in mainstream functions such as cell division, differentiation and energy metabolism, biological processes that have long been recognized as hallmarks of vitamin A action.

Understanding the function of vitamin A nutrition during development is of great clinical importance because population studies estimate that 3% of all children born in the United States have major malformations at birth (44) with 70% of these of unknown etiology, including congenital heart disease, the most prevalent human birth defect (45) . Some of the heart abnormalities obtained with retinoid receptor knockouts or resulting from insufficient vitamin A resemble the most common heart defects in humans (45) .

	FOOTNOTES

 
¹ Supported by the U.S. Department of Agriculture, the National Institutes of Health and Michigan AES.

² Manuscript received 8 December 2000.

³ Abbreviations used: CNS, central nervous system; RA, retinoic acid; RAR, retinoic acid receptor; RXR, retinoid X receptor; VAD, vitamin A-deficient.

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TOP ABSTRACT INTRODUCTION Retinoic Acid, a Critical... Model Systems for the... Heart and Blood Vessel... The Central Nervous System. Development of Limbs,... Summary and Perspectives. REFERENCES

 

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				C. A Maloney and W. D Rees Gene-nutrient interactions during fetal development Reproduction, October 1, 2005; 130(4): 401 - 410. [Abstract] [Full Text] [PDF]

				C. Zechel Requirement of Retinoic Acid Receptor Isotypes {alpha}, {beta}, and {gamma} during the Initial Steps of Neural Differentiation of PCC7 Cells Mol. Endocrinol., June 1, 2005; 19(6): 1629 - 1645. [Abstract] [Full Text] [PDF]

				C Hidalgo, C Diez, P Duque, J M Prendes, A Rodriguez, F Goyache, I Fernandez, N Facal, S Ikeda, C Alonso-Montes, et al. Oocytes recovered from cows treated with retinol become unviable as blastocysts produced in vitro Reproduction, April 1, 2005; 129(4): 411 - 421. [Abstract] [Full Text] [PDF]

				N. Ambalavanan, J. E. Tyson, K. A. Kennedy, N. I. Hansen, B. R. Vohr, L. L. Wright, W. A. Carlo, and and National Institute of Child Health and Human D Vitamin A Supplementation for Extremely Low Birth Weight Infants: Outcome at 18 to 22 Months Pediatrics, March 1, 2005; 115(3): e249 - e254. [Abstract] [Full Text] [PDF]

				M. H. Zile Vitamin A Requirement for Early Cardiovascular Morphogenesis Specification in the Vertebrate Embryo: Insights from the Avian Embryo Experimental Biology and Medicine, July 1, 2004; 229(7): 598 - 606. [Abstract] [Full Text] [PDF]

				F. A. Mic, I. O. Sirbu, and G. Duester Retinoic Acid Synthesis Controlled by Raldh2 Is Required Early for Limb Bud Initiation and Then Later as a Proximodistal Signal during Apical Ectodermal Ridge Formation J. Biol. Chem., June 18, 2004; 279(25): 26698 - 26706. [Abstract] [Full Text] [PDF]

				L. Lai, B. L. Bohnsack, K. Niederreither, and K. K. Hirschi Retinoic acid regulates endothelial cell proliferation during vasculogenesis Development, December 29, 2003; 130(26): 6465 - 6474. [Abstract] [Full Text] [PDF]

				C. Brunner, H. Laumen, P. J. Nielsen, N. Kraut, and T. Wirth Expression of the Aldehyde Dehydrogenase 2-like Gene Is Controlled by BOB.1/OBF.1 in B Lymphocytes J. Biol. Chem., November 14, 2003; 278(46): 45231 - 45239. [Abstract] [Full Text] [PDF]

				F. J. Schweigert, B. Steinhagen, J. Raila, A. Siemann, D. Peet, and U. Buscher Concentrations of carotenoids, retinol and {alpha}-tocopherol in plasma and follicular fluid of women undergoing IVF Hum. Reprod., June 1, 2003; 18(6): 1259 - 1264. [Abstract] [Full Text] [PDF]

				A. Halilagic, M. H. Zile, and M. Studer A novel role for retinoids in patterning the avian forebrain during presomite stages Development, May 15, 2003; 130(10): 2039 - 2050. [Abstract] [Full Text] [PDF]

				C. C. Wendler, A. Schmoldt, G. R. Flentke, L. C. Case, L. Quadro, W. S. Blaner, J. Lough, and S. M. Smith Increased Fibronectin Deposition in Embryonic Hearts of Retinol-Binding Protein-Null Mice Circ. Res., May 2, 2003; 92(8): 920 - 928. [Abstract] [Full Text] [PDF]

				A. D. Weston, B. Blumberg, and T. M. Underhill Active repression by unliganded retinoid receptors in development: less is sometimes more J. Cell Biol., April 28, 2003; 161(2): 223 - 228. [Abstract] [Full Text] [PDF]

				P. Duque, C. Diez, L. Royo, P.L. Lorenzo, G. Carneiro, C.O. Hidalgo, N. Facal, and E. Gomez Enhancement of developmental capacity of meiotically inhibited bovine oocytes by retinoic acid Hum. Reprod., October 1, 2002; 17(10): 2706 - 2714. [Abstract] [Full Text] [PDF]

				X. E, L. Zhang, J. Lu, P. Tso, W. S. Blaner, M. S. Levin, and E. Li Increased Neonatal Mortality in Mice Lacking Cellular Retinol-binding Protein II J. Biol. Chem., September 20, 2002; 277(39): 36617 - 36623. [Abstract] [Full Text] [PDF]