Next Article in Journal
Abdominal Obesity and Lung Cancer Risk: Systematic Review and Meta-Analysis of Prospective Studies
Next Article in Special Issue
Hepatic Retinyl Ester Hydrolases and the Mobilization of Retinyl Ester Stores
Previous Article in Journal
Influence of Bovine Whey Protein Concentrate and Hydrolysate Preparation Methods on Motility in the Isolated Rat Distal Colon
Previous Article in Special Issue
Low-Density Lipoprotein Receptor Contributes to β-Carotene Uptake in the Maternal Liver
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Nutrients
Volume 8
Issue 12
10.3390/nu8120812
nutrients-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Enzymatic Metabolism of Vitamin A in Developing Vertebrate Embryos

by
Melissa A. Metzler
and
Lisa L. Sandell
*
Department of Molecular, Cellular and Craniofacial Biology, University of Louisville, Louisville, KY 40201, USA
*
Author to whom correspondence should be addressed.
Nutrients 2016, 8(12), 812; https://doi.org/10.3390/nu8120812
Submission received: 3 November 2016 / Revised: 9 December 2016 / Accepted: 13 December 2016 / Published: 15 December 2016
(This article belongs to the Special Issue Vitamin A Update 2016)
Browse Figures
Versions Notes

Abstract

:
Embryonic development is orchestrated by a small number of signaling pathways, one of which is the retinoic acid (RA) signaling pathway. Vitamin A is essential for vertebrate embryonic development because it is the molecular precursor of the essential signaling molecule RA. The level and distribution of RA signaling within a developing embryo must be tightly regulated; too much, or too little, or abnormal distribution, all disrupt embryonic development. Precise regulation of RA signaling during embryogenesis is achieved by proteins involved in vitamin A metabolism, retinoid transport, nuclear signaling, and RA catabolism. The reversible first step in conversion of the precursor vitamin A to the active retinoid RA is mediated by retinol dehydrogenase 10 (RDH10) and dehydrogenase/reductase (SDR family) member 3 (DHRS3), two related membrane-bound proteins that functionally activate each other to mediate the interconversion of retinol and retinal. Alcohol dehydrogenase (ADH) enzymes do not contribute to RA production under normal conditions during embryogenesis. Genes involved in vitamin A metabolism and RA catabolism are expressed in tissue-specific patterns and are subject to feedback regulation. Mutations in genes encoding these proteins disrupt morphogenesis of many systems in a developing embryo. Together these observations demonstrate the importance of vitamin A metabolism in regulating RA signaling during embryonic development in vertebrates.

1. Introduction

During development an embryo must build itself from a single cell into a complex organism, a process that requires cells and tissues to communicate with each other to organize an overall body plan and morphogenesis of organs and structures. The cell interactions essential for development are mediated by a small number of molecular signaling pathways, including wnt, hedgehog (HH), fibroblast growth factor (FGF), transforming growth factor (TGF), and retinoic acid (RA) signaling. Vitamin A is essential for embryogenesis because it is the molecular precursor of the signaling molecule RA. This review will describe the metabolism of vitamin A to RA in developing embryo tissues, highlighting reversible reaction steps that occur in association with membranes, and will provide a brief overview of aspects of embryo development that depend upon RA signaling. (NOTE: Throughout the review we will follow nomenclature rules for mouse when collectively referring to genes or proteins from multiple species, and will use appropriate nomenclature rules when referring to genes or proteins from specific organisms.)
Although the molecular identity of vitamin A was not identified until the twentieth century, the value of the nutrient to human health has been appreciated since ancient times. The function, identity, and molecular nature of vitamin A were elucidated cumulatively over the course of many years and many studies (reviewed in [1,2]). The requirement for vitamin A in embryonic development was first addressed experimentally by nutritional experiments performed in the 1930s and 1940s. Newborn pigs birthed from gilts fed diets deficient in vitamin A were born without eyes, demonstrating that vitamin A is needed for eye morphogenesis [3,4,5]. Fetal and newborn rats from mothers fed vitamin A deficient diets had severe malformations. The spectrum of vitamin A deficiency defects included abnormalities in development of the eye, face, palate, heart, limb, genito-urinary tract, diaphragm, lung, salivary glands, intestinal villi, skeleton, and nasal region [6,7,8,9,10,11,12,13,14]. The array of malformations resulting from such diets became known collectively as vitamin A deficiency syndrome. Studies of avian embryos elucidated molecular and cellular mechanisms underlying defects resulting from vitamin A deficiency [15,16,17,18,19].
Developmental defects occur not only under conditions of deficiency. Exposure to excess vitamin A or its active form, RA, is equally deleterious for embryonic development as is vitamin A deficiency [20,21,22,23,24,25,26,27]. Thus, too little or too much vitamin A, or its active derivative RA, disrupts embryonic development.

2. Vitamin A is the Molecular Precursor of RA

The chemical structure of vitamin A was solved by Karrer and colleagues in 1931 [28]. Strictly applied, the term “vitamin A” describes the molecule all-trans-retinol (ROL) [29]. More loosely applied, the term can be used to refer to set of compounds closely related to ROL. Collectively ROL and its derivatives are known as “retinoids”, a term that can be applied to natural or synthetic molecules with vitamin A activity. In this review, the term retinoid refers to natural compounds only. Each retinoid is composed of a monocyclic ring with an attached isoprenoid chain (Figure 1). The individual retinoids differ with respect to the polar end group at the terminus of the chain (reviewed in [30]). ROL, the alcohol form, has a terminal –OH hydroxyl group. Retinyl esters (RE) have a terminal –O-alkyl unit. The aldehyde form of vitamin A, all-trans-retinal (RAL), has a terminal –CHO aldehyde group. RA, the acid form of vitamin A has a –COOH in the terminal position. ROL and RAL are critical for energy metabolism [31,32] and vision (reviewed in [33]). With respect to embryo development, RA is the retinoid that mediates cellular signaling and transcriptional regulation critical for pattern formation and organogenesis. RA has the most potency in rescuing the developmental defects associated with vitamin A deficiency [34]. Inversely, in excess, RA is the most potent teratogen [35].
The relationship and interconversion of the retinoid forms was described initially by Dowling and Wald [36]. ROL can be reversibly converted to RE, or to RAL (Figure 1). Additionally, RAL can be generated by cleavage of carotenoids such as β–carotene. RAL can then be oxidized to form RA [37]. The oxidation of RAL to RA is a non-reversible reaction. All retinoids are polarized and highly hydrophobic [38]. ROL localizes to membranes and lipid compartments within cells and tissues [39]. In environments such as cytosol or blood serum, retinoids are bound by proteins protecting them from aqueous surroundings.
Animals cannot synthesize any retinoids de novo but must obtain the molecules as micronutrients from the diet. Vitamin A can be taken up in two forms; “preformed vitamin A”, which refers to the retinoid molecules; or “provitamin A”, which refers to carotenoids (reviewed in [40,41]). Preformed vitamin A, predominantly in the form of ROL or RE, can be obtained from animal sources such as milk, eggs, and liver. Provitamin A carotenoids, including β-carotene, are obtained from plant sources such as sweet potato and carrots.
Embryos receive retinoids from their mother. In mammals, maternal-embryo retinoid transfer occurs via transmission of ROL or β-carotene across the placental barrier [42,43,44]. In egg-laying species, maternal-embryo retinoid transfer occurs by maternal deposition of retinoids and carotenoids to the egg yolk [45,46], and subsequent embryo uptake from the yolk. The form of retinoid stored in egg varies in different evolutionary groups. Fish eggs have more RAL than ROL, and birds and reptiles have more ROL than RAL. Once the cells of an embryo take up ROL or β-carotene, these precursors can be oxidized to RAL, and then to the active signaling molecule RA.

3. RA Signaling Occurs via RAR Nuclear Transcription Factors

The most fully elucidated mechanism of RA signaling is the canonical pathway in which RA regulates transcription by binding to specific nuclear transcription factors known as retinoic acid receptors (RARs) (Figure 2A) (reviewed in [47,48,49,50]). RARs function as heterodimers with related transcription factors retinoid X receptors (RXRs). There are three RAR subtypes, (RARα, RARβ, RARγ). Most vertebrates have three RAR genes, one for each receptor subtype. Zebrafish have two RAR alpha and two RAR gamma but no RAR beta [51]. There are typically three RXRs (RXRα, RXRβ, RXRγ), although fishes generally have one additional RXR, and the zebrafish, in particular, have duplicates of each RXR gene [52,53]. Some of the Rar and Rxr genes are expressed in specific tissues of developing embryos, while others are broadly expressed [54]. Multiple RAR/RXR heterodimeric combinations can transduce RA signaling. Mouse embryos exposed to excess RA have active signaling in nearly all cells of the embryo as detected by a transgenic reporter [55]. Ectopic expression of RAR does not result in ectopic signaling, demonstrating that RAR expression is not limiting [56]. Thus, within a given embryonic cell or tissue, the presence or absence of RA signaling is defined primarily by presence or absence of RA, and not by the expression of RARs.
In addition to their role as partners for RARs, RXRs can interact functionally with other nuclear receptors including thyroid hormone receptors, vitamin D receptor, peroxisome proliferator-activated receptors (PPARs), and others [57,58]. With respect to RA signaling, it is particularly notable that RXRs interact with PPARβ/δ, which can bind RA and transduce signal [59,60,61]. RA signaling through RXR:PPARβ/δ has been demonstrated to be important for energy homeostasis and insulin response [62], but a role for this combination of receptors in embryonic development has not been defined.
RAR/RXR heterodimers can bind constitutively to target DNA sequences known as RA response elements (RAREs) located in the enhancer regions of genes regulated by RA (Figure 2A). Typically RAREs consist of two hexamer binding “half-sites”, arranged as direct repeats (DR), inverted repeats (IR) or palindromes (Figure 2B) [63,64,65]. The half-sites may be separated by 0–10 nucleotides. The different configurations are denoted DR0, DR1, DR2, IR9, IR10, etc., depending on the relative orientation and the number of non-binding spacer nucleotides between the hexamer binding sequences. Examples of RAREs that regulate expression of genes important for embryonic development include a DR5 that is critical for controlling expression of Hoxa1 in mouse [66,67], DR2s that regulate expression of Hoxb1 [68] and Fgf8 [69], and a DR1 that regulates expression of Crabp2 [70].
The canonical model of RA signaling is that RAR/RXR heterodimers are bound to target DNA elements independent of ligand, and that RA binding activates gene transcription by releasing co-repressors and recruiting co-activating factors [71]. However, recent studies reveal that ligand-dependent activation of constitutively bound receptors is only one of many mechanisms of retinoid signaling. The canonical mode of RARs binding DNA constitutively is not universal. In some cases, RA ligand can induce RAR/RXR binding to unoccupied RAREs in cultured embryonic stem cells [72,73]. Moreover, the canonical mechanism wherein ligand binding activates gene expression is not the only mechanism of RA-mediated gene regulation. In some cases, binding of RA to RARs can cause gene repression rather than activation ([65], reviewed in [74]). RA regulation of gene expression is also not limited to interaction with RARs. RA also functions as a ligand for other nuclear receptors [59,64]. Finally, RA and RAR have alternate functions outside the nucleus unrelated to direct regulation of transcription [58,75].
The role of RAR and RXR receptors in mediating RA signaling during embryogenesis has been elucidated in part by examining the phenotype of genetic loss of function. Mutation of Rxra causes defects in formation of the eyes and heart outflow tract, phenotypes also observed in vitamin A deficiency. For the other two Rxr genes, and all three Rar genes, mutant loss of function does not cause strong embryo phenotypes when mutations are present individually. However, compound mutations of different Rar genes exhibit multiple defects. For example, compound mutation of Rara and Rarb, Rara and Rarg, or Rxra and Rxrb each cause a spectrum of embryonic phenotypes similar to that observed in vitamin A nutritional deficiency [50,76]. The lack of strong phenotype in most individual mutants of Rar and Rxr genes presumably reflects the functional redundancy of these factors.

4. Regulation of RA Signaling by Metabolic Enzymes

RA is not present uniformly throughout an embryo, and RA signaling activity does not occur equally in all cells (Figure 3). Differential distribution of RA in developing embryonic tissues of chick has been detected by direct chemical analysis [77,78]. In zebrafish differential distribution of RA has been visualized by molecular reporters that fluoresce in presence of RA [79]. Spatial distribution of RA signaling activity can also be visualized indirectly by staining for activity of transgenic reporters of canonical ligand-dependent RAR gene activation in mice and zebrafish [55,56,80].
For most key embryonic signaling pathways (Wnt, HH, FGF, TGF, etc.) the distribution of a signal within an embryo reflects the distribution of secreted protein ligand and cognate receptor. Thus, signaling by these pathways is regulated by production, secretion, and post-translational modification of proteins. In contrast, for the RA pathway, the precisely regulated level and distribution of signal activity is controlled by metabolic conversion of inactive retinoids to active RA, and by elimination of RA. Thus, the enzymes and binding proteins that mediate retinoid transport, metabolism, and catabolism are critical regulators of embryonic development.

5. ROL Enters Embryo Cells by Transport and Diffusion

Cells of a developing embryo receive retinoid from the placenta or egg yolk via the embryonic circulation. Within the blood serum ROL is bound by retinol binding protein 4 (RBP4) ([81] reviewed in [82,83]). ROL can enter the cells of an embryo by two methods; transport through a membrane transporter, or membrane diffusion (Figure 4). For the transport mechanism, RBP4 delivers ROL to the membrane transporter STRA6, which transfers the ROL into the cell and delivers it to the cellular retinol binding protein RBP1 (also known as CRBP1) [84,85,86], reviewed in [87]. Although transport of ROL into cells via the STRA6 transporter does occur, the predominant method of retinoid entry into embryo cells is membrane diffusion, and STRA6 function is not required for most aspects of embryo development. Mouse mutants with near complete elimination of RA signaling die at early organogenesis stages of development [88,89,90]. In contrast, Stra6 mutant mice are viable and fertile and have very mild phenotypes. The relatively mild phenotypes of Stra6 mutants demonstrate that STRA6 is required for maintaining vitamin A homeostasis primarily in the eye in mice [91]. In humans, mutation of Stra6 is associated with variable phenotypes, including more severe abnormalities such as pulmonary hypoplasia-diaphragmatic hernia anophthalmia-cardiac defect (PDAC) syndrome, Matthew-Wood syndrome, and syndromic microphthalimia 9 [92,93,94]. The variable defects observed in humans with Stra6 mutation are clearly deleterious, but they are less catastrophic than the post-implantation lethality that occurs from complete loss of RA signaling [88,89,90]. Thus, ROL can enter embryo cells either by transport or diffusion, but transport through STRA6 is essential only in a limited range of tissues, namely, eye, heart, diaphragm, and lung. Once inside the cell, the highly hydrophobic ROL is sequestered from the aqueous cytosol either by localization to membranes, or by binding to cellular retinol binding proteins [39,95]. RBP1 may play a role in trafficking retinoid ligands to membrane compartments within cells [96,97].

6. Reciprocal Interconversion of ROL and RAL by Membrane-Bound RDH10 and DHRS3

Inside the cells of a developing embryo ROL can be interconverted to other retinoids, either for storage as RE, or to generate active RA for signaling. Conversion of ROL to the storage form RE, is mediated by the action of enzyme lecithin:retinol acyltransferase (LRAT) ([98] reviewed in [99]). Conversion of ROL to the active signaling retinoid, RA, occurs in two sequential oxidation steps. First ROL is oxidized to the intermediate RAL, and RAL is then subsequently oxidized to generate RA. In developing embryos the first step is rate limiting and is mediated by NAD/NADP dependent retinol dehydrogenases [100]. The primary enzyme responsible for oxidation of ROL to RAL in developing embryos is retinol dehydrogenase 10 (RDH10). The physiological relevance of RDH10 in regulating RA production during embryogenesis was identified by characterization of a mouse mutant with developmental abnormalities reminiscent of vitamin A deficiency [101]. RDH10 enzymatic activity had been previously characterized in the context of the vision cycle in adult animals, but its essential biological function in generating RA during embryonic development was not initially appreciated [102]. Analysis of enzyme kinetics of human RHD10 clarified that the enzyme uses NAD+ as a cofactor and free ROL as a substrate [103].
Characterization of a number of different mouse mutants revealed that loss of RHD10 function disrupts RA production and, consequently, causes multiple developmental malformations [89,101,104,105]. The embryonic defects of Rdh10 mutants can be largely rescued by dietary supplementation with the metabolic intermediate RAL or the product RA, demonstrating that the essential function of RDH10 during embryogenesis is the production of RAL to generate RA [89,101,105].
The role RDH10 in embryonic metabolism of vitamin A is not unique to mammals. RDH10 homologs in frog and fish embryos function similarly to the RDH10 enzyme in mice. In frog embryos, overexpression of rdh10 in the presences of ROL substrate results in a phenotype similar to treatment with excess RA, while morpholino knockdown of rdh10 results in a moderate RA deficiency phenotype with eyes, head, and axis extension defects [106]. In zebrafish, morpholino knockdown of Rdh10a results in a mild RA deficiency phenotype [107]. It is possible that the loss of function phenotypes are relatively mild in these species because other SDR enzymes, such as the closely-related SDR165c (also known as RDHE2), function redundantly with Rdh10 [108]. Alternatively, it is possible that frog and fish are less dependent on RDH10 than mice because the egg embryos have more RAL available in their lipid stores than is available to mammalian embryos and they may therefore be less dependent upon oxidation of ROL [109,110]. In humans, there has been no report of mutation of RDH10 associated with developmental malformation or birth defect syndrome, likely because RDH10 function is essential for mammalian embryo survival, and loss of function is lethal prior to birth.
The RDH10-mediated oxidation of ROL to RAL is a nodal point in regulation of RA production during embryogenesis. Rdh10 gene expression is regulated by feedback from RA signaling in mice and frogs [90,106]. However, in chick, Rdh10 gene expression is not responsive to ectopic RA [111], demonstrating that RA feedback regulation on Rdh10 does not occur in all species.
RDH enzymes are members of the short chain dehydrogenase/reductases (SDR) superfamily of proteins [112]. The protein superfamily is very large and evolutionarily deep, and a systematic nomenclature system has been established to organize the related genes within, and between, species (Table 1) [113]. RDH10 is a member of the SDR16C family of SDR enzymes [113,114]. Like other SDR family members, RDH10 is a membrane-bound enzyme. It contains a conserved single-pass helical signal-anchor sequence at the N-terminus of the protein, and an additional C-terminal hydrophobic domain. Both domains contribute to localization in membrane compartments within cells [115,116]. The membrane localization of RDH10 may enable the enzyme to access free ROL (associated with a lipid membrane) as substrate, as opposed to ROL bound to RBP1 as it would be in the aqueous cytoplasm [39,117,118,119,120].
Although it is clearly important, RDH10 cannot be the only enzyme contributing to production of RAL during embryogenesis. RA production is not completely eliminated in Rdh10 null mouse mutants [89,101]. Embryos can also generate RAL from β-carotene by the action of the enzyme BCO1 (also known as CMO1, Bcmo1) [44]. Additionally, there may be SDR enzymes other than RDH10 that oxidize ROL to RAL within in an embryo. A potential candidate enzyme is SDR16C5 (also known as RDHE2), which oxidizes ROL to RAL and is closely related to RDH10 [108,121]. SDR9C family members Rdh1 or Rdh16, or SDR7C family member Rdh11 are unlikely to be responsible for embryonic RA production as mutants of these genes do not have embryonic phenotypes [122,123].
A second class of enzymes, the ADH family of cytosolic alcohol dehydrogenases, is biochemically capable of oxidizing ROL to RAL in vitro. Owing to this biochemical activity, ADH enzymes have been cited as being responsible for RA production within embryos. However, ADH family members do not contribute to embryonic vitamin A metabolism under normal conditions in vivo. Deletion of all five ADH family members does not disrupt RA production or embryonic development [124]. Instead the ADH family enzymes play a role in retinoid homeostasis under conditions of deficiency or excess in adult animals. Adult mice with a mutation of Adh1 are hypersensitive to vitamin A excess [125,126]. Mice with Adh7 (formerly Adh4) mutation are hypersensitive to vitamin A deficiency [125,127], and mice with a mutation of Adh5 (formerly Adh3) are hypersensitive to both excess and deficiency of vitamin A [128]. ADH enzymes are cytosolic, and within the cytosol ROL is bound by RBP1. ADHs can oxidize free ROL in vitro, but cannot oxidize ROL bound to RBP1 [129,130]. The likely reason that ADH enzymes do not contribute to physiological ROL metabolism under normal conditions is that there is no unbound ROL available as substrate within the cytoplasm.
In addition to being the rate-limiting step in production of RA [100,131], the conversion of ROL to RAL is also a reversible reaction. In developing embryos, the reverse of RDH10-mediated ROL oxidation, that is, the reduction of RAL to ROL, is mediated by dehydrogenase/reductase (SDR family) member 3 (DHRS3). Like RDH10, the enzymatic function of DHRS3 was originally analyzed in the context of enzymes involved in vision in the adult eye [132]. The importance of DHRS3 in retinoid metabolism during embryogenesis was identified initially on the basis of gene expression analysis of zebrafish embryos following treatment with excess RA or inhibition of RA synthesis or signaling [133]. Expression of dhrs3 was upregulated when RA was excessive and downregulated when RA synthesis or signaling was blocked, demonstrating that dhrs3 gene transcription was responsive to feedback regulation by RA. The critical role of DHRS3 in regulating metabolism of RA during embryonic development is conserved in other vertebrate species. In mice, mutation of Dhrs3 leads to depletion of stored retinoid precursors and build-up of excess RA in embryos, causing multiple malformations and late-gestation lethality [134,135]. In frogs, knock-down of Dhrs3 causes embryonic defects similar to treatment with excess RA [136].
RDH10 and DHRS3 are each oxidoreductases, redox enzymes capable of catalyzing oxidation or reduction depending on the availability of substrate and cofactor. Cofactors for such enzymes exist in different redox states, for example NAD+ (oxidized) versus NADH (reduced), or NADP+ versus NADPH. For oxidoreductases that can utilize the two different forms of the same cofactor, the direction of the redox reaction is defined by the availability of substrate and the form of cofactor available. Enzyme kinetic analysis demonstrates that RHD10 can catalyze either oxidation of ROL or reduction of RAL in vitro [103]. The preferred cofactor for RDH10 is NAD+ [103], and the preferred cofactor for DHRS3 is NADPH [132]. In adult rat liver cells, the amount of NAD+ exceeds NADH by ~1000-fold, and the amount of NADPH exceeds NADP+ by ~100-fold [137]. The high ratio of NAD+/NADH in vivo ensures that RDH10 functions primarily as an oxidase in living tissues. Conversely, the high ratio of NADPH/NADP+ ensures that DHRS3 functions primarily as a reductase.
RDH10 and DHRS3 work coordinately together to regulate interconversion of ROL and RAL during embryo development. The two enzymes are closely related proteins (Table 1). Human DHRS3 shares 54% sequence identity with human RDH10 at the amino acid level. Both are integral membrane proteins [115,116,138]. Importantly, the enzymes reciprocally activate each other when the two proteins are present together on the same membrane [135]. Thus, the reversible first step in metabolism of vitamin A occurs not in the cytosol but in close association with a membrane compartment, mediated by two membrane-bound redox enzymes that functionally interact.

7. RAL Oxidized to RA by ALDH1A Enzymes

In contrast to the reversible ROL-RAL interconversion first step of vitamin A metabolism, oxidation of RAL to the active signaling molecule RA is an irreversible reaction. Oxidation of RAL to RA is mediated by the ALDH1A family of enzymes [139,140]. Three ALDH1A family members; ALDH1A1, ALDH1A2, and ALDH1A3 (also known as RALDH1, RALDH2, and RALDH3), are expressed and active during embryonic development. Aldh1a2 is expressed earliest, from the neurulation stage onward [141], and the gene product ALDH1A2 is responsible for a majority of RAL-to-RA oxidation within a developing embryo. Targeted knock out of Aldh1a2 in mice results in near complete elimination of RA production and embryo lethality by mid-gestation [88]. Aldh1a1 and Aldh1a3 are expressed later, after the onset of facial morphogenesis. ALDH1A3 is required for morphogenesis of the eyes and nasal structures [142]. ALDH1A1 contributes for formation of the dorsal retina [143,144]. RAL, like ROL, is hydrophobic. The question of how hydrophobic RAL reaches the ALDH1 enzymes remains to be determined.

8. Fate of RA: Nuclear Transport, Catabolism, or Movement to Other Cells

Once RA is generated it can enter the nucleus to interact with RARs, it can be catabolized, or it can move to neighboring cells. There are two cellular retinoic acid binding proteins (CRABP). CRABP2 shuttles RA into the nucleus and delivers it directly to RARs [145,146,147]. CRABP1 may sequester RA from the aqueous cytoplasm, or shuttle it to catabolizing enzymes [148]. Crabp proteins are essential for hindbrain patterning in zebrafish [149]. However, in mice, mutation of Crabp2 causes only minor limb abnormalities that are mild relative to defects in RA production [150]. Mutation of Crabp1 in mouse produces no detectable embryonic phenotype [151,152]. Thus, these binding proteins may be dispensable, or other factors may compensate for their loss, during mammalian embryogenesis.
Maintaining the appropriate level and distribution of RA within developing embryonic tissues depends upon controlled elimination of RA as well as RA production. Active RA is catabolized to inactive metabolites by oxidation by CYP26 family enzymes, which are members of the cytochrome P450 superfamily of proteins [153] (reviewed in [154,155]). Two CYP26 enzymes, CYP26A1 and CYP26B1 are essential for spatially restricted clearance of RA in developing vertebrate embryos. Mutation of Cyp26a1 or Cyp26b1 in mice results in defects similar to treatment with excess RA [156,157]. A third paralog, CYP26C1, is not essential on its own, but functions redundantly with CYP26A1 [158].
RA produced in one cell can result in signaling activity in neighboring cells, thereby functioning in a paracrine manner (reviewed in [159]). The mechanism of RA movement has not been demonstrated experimentally, but could result from diffusion or transport. The ability of RA to diffuse would be consistent with a function as a morphogen, that is, action on cells at a distance from the source of production. RA could form a gradient by diffusion from a source tissue with high concentration of RA toward a sink tissue with vanishingly low concentration of RA. Source tissues could be those that express high levels of RA producing enzymes, and sink tissues could be those that express enzymes of RA catabolism. Gradients of RA have been detected by chemical analysis in chick [77,78], by direct molecular sensors [79], and by using reporters of RA signaling activity in zebrafish [160]. Computational modeling of RA gradients has identified features that make them robust (reviewed in [161]).

9. Tissue-Specific Gene Expression and Feedback Regulation

Genes involved in production of RA, including Rdh10, Dhrs3, Aldh1a1, Aldh1a2, Aldh1a3, are expressed in, or near, cells with active RA signaling [54,101,162,163,164,165,166,167]. Conversely, genes involved in RA catabolism are expressed in regions of the embryo where RA signaling is absent [167,168,169]. Many of the vitamin A metabolic, or catabolic genes are controlled by positive and negative feedback from RA signaling (reviewed in [170]). Genes that are transcriptionally regulated by feedback from RA include those involved in vitamin A metabolism and RA production [104,106,133,134,164]. Genes encoding RARs are also sensitive to feedback control [171], as are genes encoding the RA catabolizing CYP26 enzymes [172].

10. Development of Many Embryo Systems Depends upon Genes and Proteins Involved in Retinoid Transport, Metabolism, Signaling, and Catabolism

A complete description of all aspects of embryogenesis that are regulated by RA signaling is beyond the scope of this review. Table 2 provides a partial list of embryonic systems that are disrupted when genes required for retinoid metabolism, catabolism, or signaling are mutated or experimentally knocked down.

11. Summary

RA, the active metabolite of vitamin A, is a signaling molecule essential for many aspects of embryonic development. The amount and distribution of RA signaling is precisely regulated in specific tissues and specific domains of a developing embryo. Tight control of RA signaling is achieved by regulated expression of genes encoding proteins that mediate vitamin A metabolism, retinoid transport, nuclear signaling, and RA catabolism. Recent studies have highlighted the importance of the reversible first step of vitamin A metabolism, the inter-conversion of ROL and RAL mediated by RDH10 and DHRS3, two related membrane-bound SDR proteins that activate each other functionally. The mechanisms and functions of vitamin A metabolism and RA signaling have been revealed by nutritional deficiency studies, exposure to ectopic RA, and by the phenotypes of mutants in model experimental organisms. Mutations that disrupt retinoid metabolism or RA signaling cause a wide range of defects impacting nearly all parts of an embryo. Although the list of known functions of RA signaling is extensive, future studies will undoubtedly identify additional, as yet unknown, roles for RA signaling in embryonic development. Application of new large-scale sequencing technologies will likely identify new targets of direct RA transcriptional regulation. Given the exciting new observations of non-genomic functions of RA in vitro, future exploration of these novel RA functions in vivo promises to reveal interesting roles for vitamin A and its derivatives during embryonic development.

Acknowledgments

Research in the Sandell laboratory is supported by R15 DE025960 and a Competitive Enhancement Grant from University of Louisville EVPRI. MAM was supported by F31 DE022679.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Semba, R.D. On the ‘discovery’ of vitamin A. Ann. Nutr. Metab. 2012, 61, 192–198. [Google Scholar] [CrossRef] [PubMed]
  2. Wolf, G.; Carpenter, K.J. Early research into the vitamins: The work of Wilhelm stepp. J. Nutr. 1997, 127, 1255–1259. [Google Scholar] [PubMed]
  3. Hale, F. Pigs born without eye balls. J. Hered. 1933, 23, 105–106. [Google Scholar]
  4. Hale, F. The relation of vitamin A to anophthalmos in pigs. Am. J. Ophthamol. 1935, 18, 1087–1092. [Google Scholar] [CrossRef]
  5. Hale, F. The relation of vitamin A to the eye development in the pig. J. Anim. Sci. 1935, 1935, 126–128. [Google Scholar]
  6. Wilson, J.G.; Warkany, J. Malformations in the genito-urinary tract induced by maternal vitamin A deficiency in the rat. Am. J. Anat. 1948, 83, 357–407. [Google Scholar] [CrossRef] [PubMed]
  7. Deuschle, F.M.; Warkany, J. Congenital dentofacial malformations in rats induced by maternal nutritional deficiency. J. Dent. Res. 1956, 35, 674–684. [Google Scholar] [CrossRef] [PubMed]
  8. Warkany, J.; Nelson, R.C.; Schraffenberger, E. Congenital malformations induced in rats by maternal nutritional deficiency: IV. Cleft palate. Am. J. Dis. Child. 1943, 65, 882–894. [Google Scholar] [CrossRef]
  9. Wilson, J.G.; Roth, C.B.; Warkany, J. An analysis of the syndrome of malformations induced by maternal vitamin A deficiency. Effects of restoration of vitamin A at various times during gestation. Am. J. Anat. 1953, 92, 189–217. [Google Scholar] [CrossRef] [PubMed]
  10. Wilson, J.G.; Warkany, J. Cardiac and aortic arch anomalies in the offspring of vitamin A deficient rats correlated with similar human anomalies. Pediatrics 1950, 5, 708–725. [Google Scholar] [PubMed]
  11. Wilson, J.G.; Warkany, J. Aortic-arch and cardiac anomalies in the offspring of vitamin A deficient rats. Am. J. Anat. 1949, 85, 113–155. [Google Scholar] [CrossRef] [PubMed]
  12. Warkany, J.; Schraffenberger, E. Congenital malformations induced in rats by maternal vitamin A deficiency; defects of the eye. Arch. Ophthal. 1946, 35, 150–169. [Google Scholar] [CrossRef] [PubMed]
  13. See, A.W.M.; Kaiser, M.E.; White, J.C.; Clagett-Dame, M. A nutritional model of late embryonic vitamin A deficiency produces defects in organogenesis at a high penetrance and reveals new roles for the vitamin in skeletal development. Dev. Biol. 2008, 316, 171–190. [Google Scholar] [CrossRef] [PubMed]
  14. Warkany, J.; Roth, C.B. Congenital malformations induced in rats by maternal vitamin A deficiency II. Effect of varying preparatory diet upon the yield of abnormal young. J. Nutr. 1948, 35, 1–11. [Google Scholar]
  15. Maden, M.; Gale, E.; Kostetskii, I.; Zile, M. Vitamin A deficient quail embryos have half a hindbrain and other neural defects. Curr. Biol. 1996, 6, 417–426. [Google Scholar] [CrossRef]
  16. Gale, E.; Zile, M.; Maden, M. Hindbrain respecification in the retinoid-deficient quail. Mech. Dev. 1999, 89, 43–54. [Google Scholar] [CrossRef]
  17. Kostetskii, I.; Jiang, Y.; Kostetskaia, E.; Yuan, S.; Evans, T.; Zile, M. Retinoid signaling required for normal heart development regulates gata-4 in a pathway distinct from cardiomyocyte differentiation. Dev. Biol. 1999, 206, 206–218. [Google Scholar] [CrossRef] [PubMed]
  18. Ghatpande, S.; Ghatpande, A.; Sher, J.; Zile, M.H.; Evans, T. Retinoid signaling regulates primitive (yolk sac) hematopoiesis. Blood 2002, 99, 2379–2386. [Google Scholar] [CrossRef] [PubMed]
  19. Kil, S.H.; Streit, A.; Brown, S.T.; Agrawal, N.; Collazo, A.; Zile, M.H.; Groves, A.K. Distinct roles for hindbrain and paraxial mesoderm in the induction and patterning of the inner ear revealed by a study of vitamin-A-deficient quail. Dev. Biol. 2005, 285, 252–271. [Google Scholar] [CrossRef] [PubMed]
  20. Cohlan, S.Q. Excessive intake of vitamin A as a cause of congenital anomalies in the rat. Science 1953, 117, 535–536. [Google Scholar] [CrossRef] [PubMed]
  21. Lammer, E.; Chen, D.; Hoar, R.; Agnish, A.; Benke, P.; Braun, J.; Curry, C.; Fernhoff, P.; Grix, A.; Lott, I.; et al. Retinoic acid embryopathy. N. Eng. J. Med. 1985, 313, 837–841. [Google Scholar] [CrossRef] [PubMed]
  22. Knudsen, P.A. Congenital malformations of lower incisors and molars in exencephalic mouse embryos, induced by hypervitaminosis A. Acta Odontol. Scand. 1966, 24, 55–71. [Google Scholar] [CrossRef]
  23. Shenefelt, R.E. Morphogenesis of malformations in hamsters caused by retinoic acid: Relation to dose and stage at treatment. Teratology 1972, 5, 103–118. [Google Scholar] [CrossRef] [PubMed]
  24. Kochhar, D.M. Limb development in mouse embryos. I. Analysis of teratogenic effects of retinoic acid. Teratology 1973, 7, 289–295. [Google Scholar] [CrossRef] [PubMed]
  25. Newell-Morris, L.; Sirianni, J.E.; Shepard, T.H.; Fantel, A.G.; Moffett, B.C. Teratogenic effects of retinoic acid in pigtail monkeys (macaca nemestrina). II. Craniofacial features. Teratology 1980, 22, 87–101. [Google Scholar] [CrossRef] [PubMed]
  26. Fantel, A.G.; Shepard, T.H.; Newell-Morris, L.L.; Moffett, B.C. Teratogenic effects of retinoic acid in pigtail monkeys (macaca nemestrina). I. General features. Teratology 1977, 15, 65–71. [Google Scholar] [CrossRef] [PubMed]
  27. Rosa, F.W.; Wilk, A.L.; Kelsey, F.O. Vitamin A congeners. Teratology 1986, 33, 355–364. [Google Scholar] [CrossRef] [PubMed]
  28. Karrer, P.; Morf, R.; Schöpp, K. Zur kenntnis des vitamins-A aus fischtranen. Helv. Chim. Acta 1931, 14, 1036–1040. [Google Scholar] [CrossRef]
  29. Liébecq, C. Biochemical Nomenclature and Related Documents: A Compendium, 2nd ed.; Series: International union of biochemistry and molecular biology; Portland Press: London, UK, 1992. [Google Scholar]
  30. O’Byrne, S.M.; Blaner, W.S. Retinol and retinyl esters: Biochemistry and physiology. J. Lipid Res. 2013, 54, 1731–1743. [Google Scholar] [CrossRef] [PubMed]
  31. Hammerling, U. Retinol as electron carrier in redox signaling, a new frontier in vitamin A research. Hepatobiliary Surg. Nutr. 2016, 5, 15–28. [Google Scholar] [PubMed]
  32. Ziouzenkova, O.; Orasanu, G.; Sharlach, M.; Akiyama, T.E.; Berger, J.P.; Viereck, J.; Hamilton, J.A.; Tang, G.; Dolnikowski, G.G.; Vogel, S.; et al. Retinaldehyde represses adipogenesis and diet-induced obesity. Nat. Med. 2007, 13, 695–702. [Google Scholar] [CrossRef] [PubMed]
  33. Zhong, M.; Kawaguchi, R.; Kassai, M.; Sun, H. Retina, retinol, retinal and the natural history of vitamin A as a light sensor. Nutrients 2012, 4, 2069–2096. [Google Scholar] [CrossRef] [PubMed]
  34. Dersch, H.; Zile, M.H. Induction of normal cardiovascular development in the vitamin A-deprived quail embryo by natural retinoids. Dev. Biol. 1993, 160, 424–433. [Google Scholar] [CrossRef] [PubMed]
  35. Kraft, J.C.; Juchau, M.R. Correlations between conceptal concentrations of all-trans-retinoic acid and dysmorphogenesis after microinjections of all-trans-retinoic acid, 13-cis-retinoic acid, all-trans-retinoyl-beta-glucuronide, or retinol in cultured whole rat embryos. Drug Metab. Dispos. 1992, 20, 218–225. [Google Scholar] [PubMed]
  36. Dowling, J.E.; Wald, G. The biological function of vitamin A acid. Proc. Natl. Acad. Sci. USA 1960, 46, 587–608. [Google Scholar] [CrossRef] [PubMed]
  37. Emerick, R.J.; Zile, M.; DeLuca, H.F. Formation of retinoic acid from retinol in the rat. Biochem. J. 1967, 102, 606–611. [Google Scholar] [CrossRef] [PubMed]
  38. Szuts, E.Z.; Harosi, F.I. Solubility of retinoids in water. Arch. Biochem. Biophys. 1991, 287, 297–304. [Google Scholar] [CrossRef]
  39. Noy, N.; Xu, Z.J. Thermodynamic parameters of the binding of retinol to binding proteins and to membranes. Biochemistry 1990, 29, 3888–3892. [Google Scholar] [CrossRef] [PubMed]
  40. D’Ambrosio, D.N.; Clugston, R.D.; Blaner, W.S. Vitamin A metabolism: An update. Nutrients 2011, 3, 63–103. [Google Scholar] [CrossRef] [PubMed]
  41. Eroglu, A.; Harrison, E.H. Carotenoid metabolism in mammals, including man: Formation, occurrence, and function of apocarotenoids. J. Lipid Res. 2013, 54, 1719–1730. [Google Scholar] [CrossRef] [PubMed]
  42. Wassef, L.; Quadro, L. Uptake of dietary retinoids at the maternal-fetal barrier: In vivo evidence for the role of lipoprotein lipase and alternative pathways. J. Biol. Chem. 2011, 286, 32198–32207. [Google Scholar] [CrossRef] [PubMed]
  43. Quadro, L.; Hamberger, L.; Gottesman, M.E.; Wang, F.; Colantuoni, V.; Blaner, W.S.; Mendelsohn, C.L. Pathways of vitamin a delivery to the embryo: Insights from a new tunable model of embryonic vitamin A deficiency. Endocrinology 2005, 146, 4479–4490. [Google Scholar] [CrossRef] [PubMed]
  44. Kim, Y.-K.; Wassef, L.; Chung, S.; Jiang, H.; Wyss, A.; Blaner, W.S.; Quadro, L. Β-carotene and its cleavage enzyme β-carotene-15,15′-oxygenase (cmoi) affect retinoid metabolism in developing tissues. FASEB J. 2011, 25, 1641–1652. [Google Scholar] [CrossRef] [PubMed]
  45. Irie, T.; Sugimoto, T.; Ueki, N.; Senoo, H.; Seki, T. Retinoid storage in the egg of reptiles and birds. Comp. Biochem. Physiol. B. Biochem. Mol. Biol. 2010, 157, 113–118. [Google Scholar] [CrossRef] [PubMed]
  46. Lubzens, E.; Lissauer, L.; Levavi-Sivan, B.; Avarre, J.C.; Sammar, M. Carotenoid and retinoid transport to fish oocytes and eggs: What is the role of retinol binding protein? Mol. Aspects Med. 2003, 24, 441–457. [Google Scholar] [CrossRef]
  47. Chambon, P. A decade of molecular biology of retinoic acid receptors. FASEB J. 1996, 10, 940–954. [Google Scholar] [PubMed]
  48. Germain, P.; Chambon, P.; Eichele, G.; Evans, R.M.; Lazar, M.A.; Leid, M.; De Lera, A.R.; Lotan, R.; Mangelsdorf, D.J.; Gronemeyer, H. International union of pharmacology. LX. Retinoic acid receptors. Pharmacol. Rev. 2006, 58, 712–725. [Google Scholar] [CrossRef] [PubMed]
  49. Mark, M.; Ghyselinck, N.B.; Chambon, P. Function of retinoid nuclear receptors: Lessons from genetic and pharmacological dissections of the retinoic acid signaling pathway during mouse embryogenesis. Annu. Rev. Pharmacol. Toxicol. 2006, 46, 451–480. [Google Scholar] [CrossRef] [PubMed]
  50. Mark, M.; Ghyselinck, N.B.; Chambon, P. Function of retinoic acid receptors during embryonic development. Nucl. Recept. Signal. 2009, 7, e002. [Google Scholar] [CrossRef] [PubMed]
  51. Hale, L.A.; Tallafuss, A.; Yan, Y.L.; Dudley, L.; Eisen, J.S.; Postlethwait, J.H. Characterization of the retinoic acid receptor genes raraa, rarab and rarg during zebrafish development. Gene Expr. Patterns 2006, 6, 546–555. [Google Scholar] [CrossRef] [PubMed]
  52. Waxman, J.S.; Yelon, D. Comparison of the expression patterns of newly identified zebrafish retinoic acid and retinoid x receptors. Dev. Dyn. 2007, 236, 587–595. [Google Scholar] [CrossRef] [PubMed]
  53. Tallafuss, A.; Hale, L.A.; Yan, Y.L.; Dudley, L.; Eisen, J.S.; Postlethwait, J.H. Characterization of retinoid-x receptor genes rxra, rxrba, rxrbb and rxrg during zebrafish development. Gene Expr. Patterns 2006, 6, 556–565. [Google Scholar] [CrossRef] [PubMed]
  54. Dolle, P. Developmental expression of retinoic acid receptors (RARs). Nucl. Recept. Signal. 2009, 7, e006. [Google Scholar] [CrossRef] [PubMed]
  55. Rossant, J.; Zirngibl, R.; Cado, D.; Shago, M.; Goguere, V. Expression of retinoic acid response element-hsp lacz transgene defines specific domains of transcriptional activity during mouse embryogenesis. Genes Dev. 1991, 5, 1333–1344. [Google Scholar] [CrossRef] [PubMed]
  56. Waxman, J.S.; Yelon, D. Zebrafish retinoic acid receptors function as context-dependent transcriptional activators. Dev. Biol. 2011, 352, 128–140. [Google Scholar] [CrossRef] [PubMed]
  57. Germain, P.; Chambon, P.; Eichele, G.; Evans, R.M.; Lazar, M.A.; Leid, M.; De Lera, A.R.; Lotan, R.; Mangelsdorf, D.J.; Gronemeyer, H. International union of pharmacology. LXIII. Retinoid x receptors. Pharmacol. Rev. 2006, 58, 760–772. [Google Scholar] [CrossRef] [PubMed]
  58. Al Tanoury, Z.; Piskunov, A.; Rochette-Egly, C. Vitamin a and retinoid signaling: Genomic and nongenomic effects: Thematic review series: Fat-soluble vitamins: Vitamin A. J. Lipid Res. 2013, 54, 1761–1775. [Google Scholar] [CrossRef] [PubMed]
  59. Schug, T.T.; Berry, D.C.; Shaw, N.S.; Travis, S.N.; Noy, N. Opposing effects of retinoic acid on cell growth result from alternate activation of two different nuclear receptors. Cell 2007, 129, 723–733. [Google Scholar] [CrossRef] [PubMed]
  60. Schug, T.T.; Berry, D.C.; Toshkov, I.A.; Cheng, L.; Nikitin, A.Y.; Noy, N. Overcoming retinoic acid-resistance of mammary carcinomas by diverting retinoic acid from pparbeta/delta to rar. Proc. Natl. Acad. Sci. USA 2008, 105, 7546–7551. [Google Scholar] [CrossRef] [PubMed]
  61. Berry, D.C.; Noy, N. Is pparbeta/delta a retinoid receptor? PPAR Res. 2007, 2007, 73256. [Google Scholar] [CrossRef] [PubMed]
  62. Berry, D.C.; Noy, N. All-trans-retinoic acid represses obesity and insulin resistance by activating both peroxisome proliferation-activated receptor beta/delta and retinoic acid receptor. Mol. Cell. Biol. 2009, 29, 3286–3296. [Google Scholar] [CrossRef] [PubMed]
  63. Balmer, J.E.; Blomhoff, R. A robust characterization of retinoic acid response elements based on a comparison of sites in three species. J. Steroid Biochem. Mol. Biol. 2005, 96, 347–354. [Google Scholar] [CrossRef] [PubMed]
  64. Zhang, R.; Wang, Y.; Li, R.; Chen, G. Transcriptional factors mediating retinoic acid signals in the control of energy metabolism. Int. J. Mol. Sci. 2015, 16, 14210–14244. [Google Scholar] [CrossRef] [PubMed]
  65. Moutier, E.; Ye, T.; Choukrallah, M.-A.; Urban, S.; Osz, J.; Chatagnon, A.; Delacroix, L.; Langer, D.; Rochel, N.; Moras, D.; et al. Retinoic acid receptors recognize the mouse genome through binding elements with diverse spacing and topology. J. Biol. Chem. 2012, 287, 26328–26341. [Google Scholar] [CrossRef] [PubMed]
  66. Langston, A.W.; Gudas, L.J. Identification of a retinoic acid responsive enhancer 3′ of the murine homeobox gene hox-1.6. Mech. Dev. 1992, 38, 217–228. [Google Scholar] [CrossRef]
  67. Dupé, V.; Davenne, M.; Brocard, J.; Dollé, P.; Mark, M.; Dierich, A.; Chambon, P.; Rijli, F. In vivo functional analysis of the hoxa1 3′ retinoid response element (3′ RARFFE). Development 1997, 124, 399–410. [Google Scholar] [PubMed]
  68. Marshall, H.; Studer, M.; Pöpperl, H.; Aparicio, S.; Kuroiwa, A.; Brenner, S.; Krumlauf, R. A conserved retinoic acid response element required for early expression of the homeobox gene hoxb-1. Nature 1994, 370, 567–571. [Google Scholar] [CrossRef] [PubMed]
  69. Kumar, S.; Duester, G. Retinoic acid controls body axis extension by directly repressing fgf8 transcription. Development 2014, 141, 2972–2977. [Google Scholar] [CrossRef] [PubMed]
  70. Durand, B.; Saunders, M.; Leroy, P.; Leid, M.; Chambon, P. All-trans and 9-cis retinoic acid induction of crabpii transcription is mediated by rar-rxr heterodimers bound to dr1 and dr2 repeated motifs. Cell 1992, 71, 73–85. [Google Scholar] [CrossRef]
  71. Dilworth, F.J.; Chambon, P. Nuclear receptors coordinate the activities of chromatin remodeling complexes and coactivators to facilitate initiation of transcription. Oncogene 2001, 20, 3047–3054. [Google Scholar] [CrossRef] [PubMed]
  72. Mahony, S.; Mazzoni, E.O.; McCuine, S.; Young, R.A.; Wichterle, H.; Gifford, D.K. Ligand-dependent dynamics of retinoic acid receptor binding during early neurogenesis. Genome Biol. 2011, 12, R2. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Bruck, N.; Vitoux, D.; Ferry, C.; Duong, V.; Bauer, A.; de The, H.; Rochette-Egly, C. A coordinated phosphorylation cascade initiated by p38mapk/msk1 directs raralpha to target promoters. EMBO J. 2009, 28, 34–47. [Google Scholar] [CrossRef] [PubMed]
  74. Weston, A.D.; Blumberg, B.; Underhill, T.M. Active repression by unliganded retinoid receptors in development: Less is sometimes more. J. Cell Biol. 2003, 161, 223–228. [Google Scholar] [CrossRef] [PubMed]
  75. Iskakova, M.; Karbyshev, M.; Piskunov, A.; Rochette-Egly, C. Nuclear and extranuclear effects of vitamin A. Can. J. Physiol. Pharmacol. 2015, 93, 1065–1075. [Google Scholar] [CrossRef] [PubMed]
  76. Rhinn, M.; Dollé, P. Retinoic acid signalling during development. Development 2012, 139, 843–858. [Google Scholar] [CrossRef] [PubMed]
  77. Eichele, G.; Thaller, C. Characterization of concentration gradients of a morphogenetically active retinoid in the chick limb bud. J. Cell Biol. 1987, 105, 1917–1923. [Google Scholar] [CrossRef] [PubMed]
  78. Thaller, C.; Eichele, G. Identification and spatial distribution of retinoids in the developing chick limb bud. Nature 1987, 327, 625–628. [Google Scholar] [CrossRef] [PubMed]
  79. Shimozono, S.; Iimura, T.; Kitaguchi, T.; Higashijima, S.-I.; Miyawaki, A. Visualization of an endogenous retinoic acid gradient across embryonic development. Nature 2013, 496, 363–366. [Google Scholar] [CrossRef] [PubMed]
  80. Perz-Edwards, A.; Hardison, N.L.; Linney, E. Retinoic acid-mediated gene expression in transgenic reporter zebrafish. Dev. Biol. 2001, 229, 89–101. [Google Scholar] [CrossRef] [PubMed]
  81. Kanai, M.; Raz, A.; Goodman, D.S. Retinol-binding protein: The transport protein for vitamin a in human plasma. J. Clin. Investig. 1968, 47, 2025–2044. [Google Scholar] [CrossRef] [PubMed]
  82. Soprano, D.R.; Blaner, W.S. Plasma retinol-binding protein. In The Retinoids: Biology, Chemistry, and Medicine, 2nd ed.; Sporn, M.B., Roberts, A.B., Goodman, D.W., Eds.; Raven Press: New York, NY, USA, 1994. [Google Scholar]
  83. Blomhoff, R.; Blomhoff, H.K. Overview of retinoid metabolism and function. J. Neurobiol. 2006, 66, 606–630. [Google Scholar] [CrossRef] [PubMed]
  84. Kawaguchi, R.; Yu, J.; Honda, J.; Hu, J.; Whitelegge, J.; Ping, P.; Wiita, P.; Bok, D.; Sun, H. A membrane receptor for retinol binding protein mediates cellular uptake of vitamin A. Science 2007, 315, 820–825. [Google Scholar] [CrossRef] [PubMed]
  85. Kawaguchi, R.; Zhong, M.; Kassai, M.; Ter-Stepanian, M.; Sun, H. Stra6-catalyzed vitamin A influx, efflux, and exchange. J. Membr. Biol. 2012, 245, 731–745. [Google Scholar] [CrossRef] [PubMed]
  86. Kawaguchi, R.; Yu, J.; Ter-Stepanian, M.; Zhong, M.; Cheng, G.; Yuan, Q.; Jin, M.; Travis, G.H.; Ong, D.; Sun, H. Receptor-mediated cellular uptake mechanism that couples to intracellular storage. ACS Chem. Biol. 2011, 6, 1041–1051. [Google Scholar] [CrossRef] [PubMed]
  87. Kelly, M.; von Lintig, J. Stra6: Role in cellular retinol uptake and efflux. Hepatobiliary Surg. Nutr. 2015, 4, 229–242. [Google Scholar] [PubMed]
  88. Niederreither, K.; Subbarayan, V.; Dollé, P.; Chambon, P. Embryonic retinoic acid synthesis is essential for early mouse post-implantation development. Nat. Genet. 1999, 21, 444–448. [Google Scholar] [CrossRef] [PubMed]
  89. Rhinn, M.; Schuhbaur, B.; Niederreither, K.; Dolle, P. Involvement of retinol dehydrogenase 10 in embryonic patterning and rescue of its loss of function by maternal retinaldehyde treatment. Proc. Natl. Acad. Sci. USA 2011, 108, 16687–16692. [Google Scholar] [CrossRef] [PubMed]
  90. Sandell, L.L.; Lynn, M.L.; Inman, K.E.; McDowell, W.; Trainor, P.A. Rdh10 oxidation of vitamin A is a critical control step in synthesis of retinoic acid during mouse embryogenesis. PLoS ONE 2012, 7, e30698. [Google Scholar] [CrossRef] [PubMed]
  91. Berry, D.C.; Jacobs, H.; Marwarha, G.; Gely-Pernot, A.; O’Byrne, S.M.; DeSantis, D.; Klopfenstein, M.; Feret, B.; Dennefeld, C.; Blaner, W.S.; et al. The STRA6 receptor is essential for retinol-binding protein-induced insulin resistance but not for maintaining vitamin A homeostasis in tissues other than the eye. J. Biol. Chem. 2013, 288, 24528–24539. [Google Scholar] [CrossRef] [PubMed]
  92. Golzio, C.; Martinovic-Bouriel, J.; Thomas, S.; Mougou-Zrelli, S.; Grattagliano-Bessières, B.; Bonnière, M.; Delahaye, S.; Munnich, A.; Encha-Razavi, F.; Lyonnet, S.; et al. Matthew-Wood syndrome is caused by truncating mutations in the retinol-binding protein receptor gene Stra6. Am. J. Hum. Genet. 2007, 80, 1179–1187. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  93. Marcadier, J.L.; Mears, A.J.; Woods, E.A.; Fisher, J.; Airheart, C.; Qin, W.; Beaulieu, C.L.; Dyment, D.A.; Innes, A.M.; Curry, C.J. A novel mutation in two Hmong families broadens the range of STRA6-related malformations to include contractures and camptodactyly. Am. J. Med. Genet. A 2016, 170a, 11–18. [Google Scholar] [CrossRef] [PubMed]
  94. Pasutto, F.; Sticht, H.; Hammersen, G.; Gillessen-Kaesbach, G.; Fitzpatrick, D.R.; Nurnberg, G.; Brasch, F.; Schirmer-Zimmermann, H.; Tolmie, J.L.; Chitayat, D.; et al. Mutations in STRA6 cause a broad spectrum of malformations including anophthalmia, congenital heart defects, diaphragmatic hernia, alveolar capillary dysplasia, lung hypoplasia, and mental retardation. Am. J. Hum. Genet. 2007, 80, 550–560. [Google Scholar] [CrossRef] [PubMed]
  95. Noy, N. Retinoid-binding proteins: Mediators of retinoid action. Biochem. J. 2000, 348, 481–495. [Google Scholar] [CrossRef] [PubMed]
  96. Jiang, W.; Napoli, J.L. Reorganization of cellular retinol-binding protein type 1 and lecithin:Retinol acyltransferase during retinyl ester biosynthesis. Biochim. Biophys. Acta 2012, 1820, 859–869. [Google Scholar] [CrossRef] [PubMed]
  97. Herr, F.M.; Li, E.; Weinberg, R.B.; Cook, V.R.; Storch, J. Differential mechanisms of retinoid transfer from cellular retinol binding proteins types I and II to phospholipid membranes. J. Biol. Chem. 1999, 274, 9556–9563. [Google Scholar] [CrossRef] [PubMed]
  98. Kim, Y.K.; Wassef, L.; Hamberger, L.; Piantedosi, R.; Palczewski, K.; Blaner, W.S.; Quadro, L. Retinyl ester formation by lecithin: Retinol acyltransferase is a key regulator of retinoid homeostasis in mouse embryogenesis. J. Biol. Chem. 2008, 283, 5611–5621. [Google Scholar] [CrossRef] [PubMed]
  99. Spiegler, E.; Kim, Y.K.; Wassef, L.; Shete, V.; Quadro, L. Maternal-fetal transfer and metabolism of vitamin A and its precursor β-carotene in the developing tissues. Biochim. Biophy. Acta 2012, 1821, 88–98. [Google Scholar] [CrossRef] [PubMed]
  100. Chen, H.; Namkung, M.J.; Juchau, M.R. Biotransformation of all-trans-retinol and all-trans-retinal to all-trans-retinoic acid in rat conceptal homogenates. Biochem. Pharmacol. 1995, 50, 1257–1264. [Google Scholar] [CrossRef]
  101. Sandell, L.L.; Sanderson, B.W.; Moiseyev, G.; Johnson, T.; Mushegian, A.; Young, K.; Rey, J.P.; Ma, J.X.; Staehling-Hampton, K.; Trainor, P.A. Rdh10 is essential for synthesis of embryonic retinoic acid and is required for limb, craniofacial, and organ development. Genes Dev. 2007, 21, 1113–1124. [Google Scholar] [CrossRef] [PubMed]
  102. Wu, B.X.; Moiseyev, G.; Chen, Y.; Rohrer, B.; Crouch, R.K.; Ma, J.X. Identification of rdh10, an all-trans retinol dehydrogenase, in retinal muller cells. Investig. Ophthalmol. Vis. Sci. 2004, 45, 3857–3862. [Google Scholar] [CrossRef] [PubMed]
  103. Belyaeva, O.V.; Johnson, M.P.; Kedishvili, N.Y. Kinetic analysis of human enzyme rdh10 defines the characteristics of a physiologically relevant retinol dehydrogenase. J. Biol. Chem. 2008, 283, 20299–20308. [Google Scholar] [CrossRef] [PubMed]
  104. Sandell, L.L. Regulated metabolism of vitamin a by retinol dehydrogenase 10 is critical for embryonic development of the heart. FASEB J. 2012, 26, S339.3. [Google Scholar]
  105. Ashique, A.M.; May, S.R.; Kane, M.A.; Folias, A.E.; Phamluong, K.; Choe, Y.; Napoli, J.L.; Peterson, A.S. Morphological defects in a novel rdh10 mutant that has reduced retinoic acid biosynthesis and signaling. Genesis 2012, 50, 415–423. [Google Scholar] [CrossRef] [PubMed]
  106. Strate, I.; Min, T.H.; Iliev, D.; Pera, E.M. Retinol dehydrogenase 10 is a feedback regulator of retinoic acid signalling during axis formation and patterning of the central nervous system. Development 2009, 136, 461–472. [Google Scholar] [CrossRef] [PubMed]
  107. D’Aniello, E.; Ravisankar, P.; Waxman, J.S. Rdh10a provides a conserved critical step in the synthesis of retinoic acid during zebrafish embryogenesis. PLoS ONE 2015, 10, e0138588. [Google Scholar] [CrossRef] [PubMed]
  108. Belyaeva, O.V.; Lee, S.A.; Adams, M.K.; Chang, C.; Kedishvili, N.Y. Short chain dehydrogenase/reductase rdhe2 is a novel retinol dehydrogenase essential for frog embryonic development. J. Biol. Chem. 2012, 287, 9061–9071. [Google Scholar] [CrossRef] [PubMed]
  109. Costaridis, P.; Horton, C.; Zeitlinger, J.; Holder, N.; Maden, M. Endogenous retinoids in the zebrafish embryo and adult. Dev. Dyn. 1996, 205, 41–51. [Google Scholar] [CrossRef]
  110. Levi, L.; Ziv, T.; Admon, A.; Levavi-Sivan, B.; Lubzens, E. Insight into molecular pathways of retinal metabolism, associated with vitellogenesis in zebrafish. Am. J. Physiol. Endocrinol. Metab. 2012, 302, E626–E644. [Google Scholar] [CrossRef] [PubMed]
  111. Reijntjes, S.; Zile, M.H.; Maden, M. The expression of Stra6 and Rdh10 in the avian embryo and their contribution to the generation of retinoid signatures. Int. J. Dev. Biol. 2010, 54, 1267–1275. [Google Scholar] [CrossRef] [PubMed]
  112. Parés, X.; Farrés, J.; Kedishvili, N.; Duester, G. Medium- and short-chain dehydrogenase/reductase gene and protein families. Cell. Mol. Life Sci. 2008, 65, 3936–3949. [Google Scholar] [CrossRef] [PubMed]
  113. Persson, B.; Kallberg, Y.; Bray, J.E.; Bruford, E.; Dellaporta, S.L.; Favia, A.D.; Duarte, R.G.; Jornvall, H.; Kavanagh, K.L.; Kedishvili, N.; et al. The sdr (short-chain dehydrogenase/reductase and related enzymes) nomenclature initiative. Chem. Biol. Interact. 2009, 178, 94–98. [Google Scholar] [CrossRef] [PubMed]
  114. Kedishvili, N.Y. Enzymology of retinoic acid biosynthesis and degradation: Thematic review series: Fat-soluble vitamins: Vitamin A. J. Lipid Res. 2013, 54, 1744–1760. [Google Scholar] [CrossRef] [PubMed]
  115. Takahashi, Y.; Moiseyev, G.; Farjo, K.; Ma, J.X. Characterization of key residues and membrane association domains in retinol dehydrogenase 10. Biochem. J. 2009, 419. [Google Scholar] [CrossRef] [PubMed]
  116. Jiang, W.; Napoli, J.L. The retinol dehydrogenase rdh10 localizes to lipid droplets during acyl ester biosynthesis. J. Biol. Chem. 2013, 288, 589–597. [Google Scholar] [CrossRef] [PubMed]
  117. Noy, N.; Xu, Z.J. Interactions of retinol with binding proteins: Implications for the mechanism of uptake by cells. Biochemistry 1990, 29, 3878–3883. [Google Scholar] [CrossRef] [PubMed]
  118. Noy, N.; Blaner, W.S. Interactions of retinol with binding proteins: Studies with rat cellular retinol-binding protein and with rat retinol-binding protein. Biochemistry 1991, 30, 6380–6386. [Google Scholar] [CrossRef] [PubMed]
  119. Fex, G.; Johannesson, G. Studies of the spontaneous transfer of retinol from the retinol:Retinol-binding protein complex to unilamellar liposomes. Biochim. Biophys. Acta 1987, 901, 255–264. [Google Scholar] [CrossRef]
  120. Fex, G.; Johannesson, G. Retinol transfer across and between phospholipid bilayer membranes. Biochim. Biophys. Acta 1988, 944, 249–255. [Google Scholar] [CrossRef]
  121. Adams, M.K.; Lee, S.A.; Belyaeva, O.V.; Wu, L.; Kedishvili, N.Y. Characterization of human short chain dehydrogenase/reductase sdr16c family members related to retinol dehydrogenase 10. Chem. Biol. Interact. 2016. [Google Scholar] [CrossRef] [PubMed]
  122. Zhang, M.; Hu, P.; Krois, C.R.; Kane, M.A.; Napoli, J.L. Altered vitamin A homeostasis and increased size and adiposity in the rdh1-null mouse. FASEB J. 2007, 21, 2886–2896. [Google Scholar] [CrossRef] [PubMed]
  123. Kim, T.S.; Maeda, A.; Maeda, T.; Heinlein, C.; Kedishvili, N.; Palczewski, K.; Nelson, P.S. Delayed dark adaptation in 11-cis-retinol dehydrogenase-deficient mice: A role of rdh11 in visual processes in vivo. J. Biol. Chem. 2005, 280, 8694–8704. [Google Scholar] [CrossRef] [PubMed]
  124. Kumar, S.; Sandell, L.L.; Trainor, P.A.; Koentgen, F.; Duester, G. Alcohol and aldehyde dehydrogenases: Retinoid metabolic effects in mouse knockout models. Biochim. Biophys. Acta 2012, 1821, 198–205. [Google Scholar] [CrossRef] [PubMed]
  125. Molotkov, A.; Deltour, L.; Foglio, M.H.; Cuenca, A.E.; Duester, G. Distinct retinoid metabolic functions for alcohol dehydrogenase genes adh1 and adh4 in protection against vitamin A toxicity or deficiency revealed in double null mutant mice. J. Biol. Chem. 2002, 277, 13804–13811. [Google Scholar] [CrossRef] [PubMed]
  126. Molotkov, A.; Fan, X.; Duester, G. Excessive vitamin A toxicity in mice genetically deficient in either alcohol dehydrogenase adh1 or adh3. Eur. J. Biochem. 2002, 269, 2607–2612. [Google Scholar] [CrossRef] [PubMed]
  127. Deltour, L.; Foglio, M.H.; Duester, G. Impaired retinol utilization in adh4 alcohol dehydrogenase mutant mice. Dev. Genet. 1999, 25, 1–10. [Google Scholar] [CrossRef]
  128. Molotkov, A.; Fan, X.; Deltour, L.; Foglio, M.H.; Martras, S.; Farres, J.; Pares, X.; Duester, G. Stimulation of retinoic acid production and growth by ubiquitously expressed alcohol dehydrogenase adh3. Proc. Natl. Acad. Sci. USA 2002, 99, 5337–5342. [Google Scholar] [CrossRef] [PubMed]
  129. Napoli, J.L. Physiological insights into all-trans-retinoic acid biosynthesis. Biochim. Biophys. Acta 2012, 1821, 152–167. [Google Scholar] [CrossRef] [PubMed]
  130. Farjo, K.M.; Moiseyev, G.; Nikolaeva, O.; Sandell, L.L.; Trainor, P.A.; Ma, J.X. Rdh10 is the primary enzyme responsible for the first step of embryonic vitamin A metabolism and retinoic acid synthesis. Dev. Biol. 2011, 357, 347–355. [Google Scholar] [CrossRef] [PubMed]
  131. Napoli, J.L. Retinol metabolism in llc-pk1 cells. Characterization of retinoic acid synthesis by an established mammalian cell line. J. Biol. Chem. 1986, 261, 13592–13597. [Google Scholar] [PubMed]
  132. Haeseleer, F.; Huang, J.; Lebioda, L.; Saari, J.C.; Palczewski, K. Molecular characterization of a novel short-chain dehydrogenase/reductase that reduces all-trans-retinal. J. Biol. Chem. 1998, 273, 21790–21799. [Google Scholar] [CrossRef] [PubMed]
  133. Feng, L.; Hernandez, R.E.; Waxman, J.S.; Yelon, D.; Moens, C.B. Dhrs3a regulates retinoic acid biosynthesis through a feedback inhibition mechanism. Dev. Biol. 2010, 338, 1–14. [Google Scholar] [CrossRef] [PubMed]
  134. Billings, S.E.; Pierzchalski, K.; Butler Tjaden, N.E.; Pang, X.Y.; Trainor, P.A.; Kane, M.A.; Moise, A.R. The retinaldehyde reductase dhrs3 is essential for preventing the formation of excess retinoic acid during embryonic development. FASEB J. 2013, 27, 4877–4889. [Google Scholar] [CrossRef] [PubMed]
  135. Adams, M.K.; Belyaeva, O.V.; Wu, L.; Kedishvili, N.Y. The retinaldehyde reductase activity of dhrs3 is reciprocally activated by retinol dehydrogenase 10 to control retinoid homeostasis. J. Biol. Chem. 2014, 289, 14868–14880. [Google Scholar] [CrossRef] [PubMed]
  136. Kam, R.K.; Shi, W.; Chan, S.O.; Chen, Y.; Xu, G.; Lau, C.B.; Fung, K.P.; Chan, W.Y.; Zhao, H. Dhrs3 protein attenuates retinoic acid signaling and is required for early embryonic patterning. J. Biol. Chem. 2013, 288, 31477–31487. [Google Scholar] [CrossRef] [PubMed]
  137. Veech, R.L.; Eggleston, L.V.; Krebs, H.A. The redox state of free nicotinamide-adenine dinucleotide phosphate in the cytoplasm of rat liver. Biochem. J. 1969, 115, 609–619. [Google Scholar] [CrossRef] [PubMed]
  138. Lundova, T.; Zemanova, L.; Malcekova, B.; Skarka, A.; Stambergova, H.; Havrankova, J.; Safr, M.; Wsol, V. Molecular and biochemical characterisation of human short-chain dehydrogenase/reductase member 3 (dhrs3). Chem. Biol. Interact. 2015, 234, 178–187. [Google Scholar] [CrossRef] [PubMed]
  139. Penzes, P.; Wang, X.; Napoli, J.L. Enzymatic characteristics of retinal dehydrogenase type I expressed in escherichia coli. Biochim. Biophys. Acta 1997, 1342, 175–181. [Google Scholar] [CrossRef]
  140. Zhao, D.; McCaffery, P.; Ivins, K.J.; Neve, R.L.; Hogan, P.; Chin, W.W.; Drager, U.C. Molecular identification of a major retinoic-acid-synthesizing enzyme, a retinaldehyde-specific dehydrogenase. Eur. J. Biochem. 1996, 240, 15–22. [Google Scholar] [CrossRef] [PubMed]
  141. Moss, J.; Xavier-Neto, J.; Shapiro, M.; Nayeem, S.; McCaffery, P.; Drägger, U.C.; Rosenthal, N. Dynamic patterns of retinoic acid synthesis and response in the developing mammalian heart. Dev. Biol. 1998, 199, 55–71. [Google Scholar] [CrossRef] [PubMed]
  142. Dupe, V.; Matt, N.; Garnier, J.M.; Chambon, P.; Mark, M.; Ghyselinck, N.B. A newborn lethal defect due to inactivation of retinaldehyde dehydrogenase type 3 is prevented by maternal retinoic acid treatment. Proc. Natl. Acad. Sci. USA 2003, 100, 14036–14041. [Google Scholar] [CrossRef] [PubMed]
  143. Matt, N.; Dupe, V.; Garnier, J.M.; Dennefeld, C.; Chambon, P.; Mark, M.; Ghyselinck, N.B. Retinoic acid-dependent eye morphogenesis is orchestrated by neural crest cells. Development 2005, 132, 4789–4800. [Google Scholar] [CrossRef] [PubMed]
  144. Molotkov, A.; Molotkova, N.; Duester, G. Retinoic acid guides eye morphogenetic movements via paracrine signaling but is unnecessary for retinal dorsoventral patterning. Development 2006, 133, 1901–1910. [Google Scholar] [CrossRef] [PubMed]
  145. Budhu, A.S.; Noy, N. Direct channeling of retinoic acid between cellular retinoic acid-binding protein II and retinoic acid receptor sensitizes mammary carcinoma cells to retinoic acid-induced growth arrest. Mol. Cell. Biol. 2002, 22, 2632–2641. [Google Scholar] [CrossRef] [PubMed]
  146. Dong, D.; Ruuska, S.E.; Levinthal, D.J.; Noy, N. Distinct roles for cellular retinoic acid-binding proteins I and ii in regulating signaling by retinoic acid. J. Biol. Chem. 1999, 274, 23695–23698. [Google Scholar] [CrossRef] [PubMed]
  147. Sessler, R.J.; Noy, N. A ligand-activated nuclear localization signal in cellular retinoic acid binding protein-II. Mol. Cell 2005, 18, 343–353. [Google Scholar] [CrossRef] [PubMed]
  148. Fiorella, P.D.; Napoli, J.L. Microsomal retinoic acid metabolism. Effects of cellular retinoic acid-binding protein (type I) and c18-hydroxylation as an initial step. J. Biol. Chem. 1994, 269, 10538–10544. [Google Scholar] [PubMed]
  149. Cai, A.Q.; Radtke, K.; Linville, A.; Lander, A.D.; Nie, Q.; Schilling, T.F. Cellular retinoic acid-binding proteins are essential for hindbrain patterning and signal robustness in zebrafish. Development 2012, 139, 2150–2155. [Google Scholar] [CrossRef] [PubMed]
  150. Lampron, C.; Rochette-Egly, C.; Gorry, P.; Dolle, P.; Mark, M.; Lufkin, T.; LeMeur, M.; Chambon, P. Mice deficient in cellular retinoic acid binding protein II (crabpII) or in both crabpi and crabpii are essentially normal. Development 1995, 121, 539–548. [Google Scholar] [PubMed]
  151. de Bruijn, D.R.; Oerlemans, F.; Hendriks, W.; Baats, E.; Ploemacher, R.; Wieringa, B.; Geurts van Kessel, A. Normal development, growth and reproduction in cellular retinoic acid binding protein-I (crabpI) null mutant mice. Differentiation 1994, 58, 141–148. [Google Scholar] [CrossRef] [PubMed]
  152. Gorry, P.; Lufkin, T.; Dierich, A.; Rochette-Egly, C.; Decimo, D.; Dolle, P.; Mark, M.; Durand, B.; Chambon, P. The cellular retinoic acid binding protein I is dispensable. Proc. Natl. Acad. Sci. USA 1994, 91, 9032–9036. [Google Scholar] [CrossRef] [PubMed]
  153. Chithalen, J.V.; Luu, L.; Petkovich, M.; Jones, G. Hplc-ms/ms analysis of the products generated from all-trans-retinoic acid using recombinant human cyp26a. J. Lipid Res. 2002, 43, 1133–1142. [Google Scholar] [CrossRef] [PubMed]
  154. Pennimpede, T.; Cameron, D.A.; MacLean, G.A.; Li, H.; Abu-Abed, S.; Petkovich, M. The role of cyp26 enzymes in defining appropriate retinoic acid exposure during embryogenesis. Birth Defects Res. A Clin. Mol. Teratol. 2010, 88, 883–894. [Google Scholar] [CrossRef] [PubMed]
  155. Ross, A.C.; Zolfaghari, R. Cytochrome p450s in the regulation of cellular retinoic acid metabolism. Annu. Rev. Nutr. 2011, 31, 65–87. [Google Scholar] [CrossRef] [PubMed]
  156. Sakai, Y.; Meno, C.; Fujii, H.; Nishino, J.; Shiratori, H.; Saijoh, Y.; Rossant, J.; Hamada, H. The retinoic acid-inactivating enzyme cyp26 is essential for establishing an uneven distribution of retinoic acid along the anterio-posterior axis within the mouse embryo. Genes Dev. 2001, 15, 213–225. [Google Scholar] [CrossRef] [PubMed]
  157. Abu-Abed, S.; Dolle, P.; Metzger, D.; Beckett, B.; Chambon, P.; Petkovich, M. The retinoic acid-metabolizing enzyme, cyp26a1, is essential for normal hindbrain patterning, vertebral identity, and development of posterior structures. Genes Dev. 2001, 15, 226–240. [Google Scholar] [CrossRef] [PubMed]
  158. Uehara, M.; Yashiro, K.; Mamiya, S.; Nishino, J.; Chambon, P.; Dolle, P.; Sakai, Y. Cyp26a1 and cyp26c1 cooperatively regulate anterior-posterior patterning of the developing brain and the production of migratory cranial neural crest cells in the mouse. Dev. Biol. 2007, 302, 399–411. [Google Scholar] [CrossRef] [PubMed]
  159. Duester, G. Retinoic acid synthesis and signaling during early organogenesis. Cell 2008, 134, 921–931. [Google Scholar] [CrossRef] [PubMed]
  160. White, R.J.; Nie, Q.; Lander, A.D.; Schilling, T.F. Complex regulation of cyp26a1 creates a robust retinoic acid gradient in the zebrafish embryo. PLoS Biol. 2007, 5, e304. [Google Scholar] [CrossRef] [PubMed]
  161. Schilling, T.F.; Nie, Q.; Lander, A.D. Dynamics and precision in retinoic acid morphogen gradients. Curr. Opin. Genet. Dev. 2012, 22, 562–569. [Google Scholar] [CrossRef] [PubMed]
  162. Ruberte, E.; Dolle, P.; Chambon, P.; Morriss-Kay, G. Retinoic acid receptors and cellular retinoid binding proteins II. Their differential pattern of transcription during early morphogenesis in mouse embryos. Development 1991, 111, 45–60. [Google Scholar] [PubMed]
  163. Cammas, L.; Romand, R.; Fraulob, V.; Mura, C.; Dolle, P. Expression of the murine retinol dehydrogenase 10 (rdh10) gene correlates with many sites of retinoid signalling during embryogenesis and organ differentiation. Dev. Dyn. 2007, 236, 2899–2908. [Google Scholar] [CrossRef] [PubMed]
  164. Niederreither, K.; McCaffery, P.; Drager, U.C.; Chambon, P.; Dolle, P. Restricted expression and retinoic acid-induced downregulation of the retinaldehyde dehydrogenase type 2 (raldh-2) gene during mouse development. Mech. Dev. 1997, 62, 67–78. [Google Scholar] [CrossRef]
  165. Ruberte, E.; Dolle, P.; Krust, A.; Zelent, A.; Morriss-Kay, G.; Chambon, P. Specific spatial and temporal distribution of retinoic acid receptor gamma transcripts during mouse embryogenesis. Development 1990, 108, 213–222. [Google Scholar] [PubMed]
  166. Romand, R.; Kondo, T.; Cammas, L.; Hashino, E.; Dolle, P. Dynamic expression of the retinoic acid-synthesizing enzyme retinol dehydrogenase 10 (rdh10) in the developing mouse brain and sensory organs. J. Comp. Neurol. 2008, 508, 879–892. [Google Scholar] [CrossRef] [PubMed]
  167. Reijntjes, S.; Blentic, A.; Gale, E.; Maden, M. The control of morphogen signalling: Regulation of the synthesis and catabolism of retinoic acid in the developing embryo. Dev. Biol. 2005, 285, 224–237. [Google Scholar] [CrossRef] [PubMed]
  168. Tahayato, A.; Dollé, P.; Petkovich, M. Cyp26c1 encodes a novel retinoic acid-metabolizing enzyme expressed in the hindbrain, inner ear, first branchial arch and tooth buds during murine development. Gene Expr. Patterns 2003, 3, 449–454. [Google Scholar] [CrossRef]
  169. Abu-Abed, S.; MacLean, G.; Fraulob, V.; Chambon, P.; Petkovich, M.; Dolle, P. Differential expression of the retinoic acid-metabolizing enzymes cyp26a1 and cyp26b1 during murine organogenesis. Mech. Dev. 2002, 110, 173–177. [Google Scholar] [CrossRef]
  170. D’Aniello, E.; Waxman, J.S. Input overload: Contributions of retinoic acid signaling feedback mechanisms to heart development and teratogenesis. Dev. Dyn. 2015, 244, 513–523. [Google Scholar] [CrossRef] [PubMed]
  171. D’Aniello, E.; Rydeen, A.B.; Anderson, J.L.; Mandal, A.; Waxman, J.S. Depletion of retinoic acid receptors initiates a novel positive feedback mechanism that promotes teratogenic increases in retinoic acid. PLoS Genet. 2013, 9, 1–13. [Google Scholar] [CrossRef] [PubMed]
  172. Emoto, Y.; Wada, H.; Okamoto, H.; Kudo, A.; Imai, Y. Retinoic acid-metabolizing enzyme cyp26a1 is essential for determining territories of hindbrain and spinal cord in zebrafish. Dev. Biol. 2005, 278, 415–427. [Google Scholar] [CrossRef] [PubMed]
  173. Glover, J.C.; Renaud, J.S.; Rijli, F.M. Retinoic acid and hindbrain patterning. J. Neurobiol. 2006, 66, 705–725. [Google Scholar] [CrossRef] [PubMed]
  174. Niederreither, K.; Vermot, J.; Schuhbaur, B.; Chambon, P.; Dollé, P. Retinoic acid synthesis and hindbrain patterning in the mouse embryo. Development 2000, 127, 75–85. [Google Scholar] [PubMed]
  175. Grandel, H.; Lun, K.; Rauch, G.J.; Rhinn, M.; Piotrowski, T.; Houart, C.; Sordino, P.; Kuchler, A.M.; Schulte-Merker, S.; Geisler, R.; et al. Retinoic acid signalling in the zebrafish embryo is necessary during pre-segmentation stages to pattern the anterior-posterior axis of the cns and to induce a pectoral fin bud. Development 2002, 129, 2851–2865. [Google Scholar] [PubMed]
  176. Begemann, G.; Schilling, T.F.; Rauch, G.J.; Geisler, R.; Ingham, P.W. The zebrafish neckless mutation reveals a requirement for raldh2 in mesodermal signals that pattern the hindbrain. Development 2001, 128, 3081–3094. [Google Scholar] [PubMed]
  177. Dupé, V.; Ghyselinck, N.; Wendling, O.; Chambon, P.; mark, M. Key roles of retinoic acid receptors alpha and beta in the patterning of the caudal hindbrain, pharyngeal arches and otocyst in the mouse. Development 1999, 126, 5051–5059. [Google Scholar] [PubMed]
  178. Wendling, O.; Ghyselinck, N.B.; Chambon, P.; Mark, M. Roles of retinoic acid receptors in early embryonic morphogenesis and hindbrain patterning. Development 2001, 128, 2031–2038. [Google Scholar] [PubMed]
  179. Lohnes, D.; Kastner, P.; Dierich, A.; Mark, M.; LeMeur, M.; Chambon, P. Function of the retinoic acid receptor gamma in the mouse. Cell 1993, 73, 643–658. [Google Scholar] [CrossRef]
  180. Lohnes, D.; Mark, M.; Mendelsohn, C.; Dolle, P.; Dierich, A.; Gorry, P.; Gansmuller, A.; Chambon, P. Function of the retinoic acid receptors (RARS) during development (I). Craniofacial and skeletal abnormalities in rar double mutants. Development 1994, 120, 2723–2748. [Google Scholar] [PubMed]
  181. Cunningham, T.J.; Zhao, X.; Sandell, L.L.; Evans, S.M.; Trainor, P.A.; Duester, G. Antagonism between retinoic acid and fibroblast growth factor signaling during limb development. Cell Rep. 2013, 3, 1503–1511. [Google Scholar] [CrossRef] [PubMed]
  182. Zhao, X.; Sirbu, I.O.; Mic, F.A.; Molotkova, N.; Molotkov, A.; Kumar, S.; Duester, G. Retinoic acid promotes limb induction through effects on body axis extension but is unnecessary for limb patterning. Curr. Biol. 2009, 19, 1050–1057. [Google Scholar] [CrossRef] [PubMed]
  183. Cunningham, T.J.; Chatzi, C.; Sandell, L.L.; Trainor, P.A.; Duester, G. Rdh10 mutants deficient in limb field retinoic acid signaling exhibit normal limb patterning but display interdigital webbing. Dev. Dyn. 2011, 240, 1142–1150. [Google Scholar] [CrossRef] [PubMed]
  184. Niederreither, K.; Vermot, J.; Schuhbaur, B.; Chambon, P.; Dolle, P. Embryonic retinoic acid synthesis is required for forelimb growth and anteroposterior patterning in the mouse. Development 2002, 129, 3563–3574. [Google Scholar] [PubMed]
  185. Ghyselinck, N.B.; Dupe, V.; Dierich, A.; Messaddeq, N.; Garnier, J.M.; Rochette-Egly, C.; Chambon, P.; Mark, M. Role of the retinoic acid receptor beta (rarbeta) during mouse development. Int. J. Dev. Biol. 1997, 41, 425–447. [Google Scholar] [PubMed]
  186. Mendelsohn, C.; Lohnes, D.; Decimo, D.; Lufkin, T.; LeMeur, M.; Chambon, P.; Mark, M. Function of the retinoic acid receptors (RARS) during development (II). Multiple abnormalities at various stages of organogenesis in rar double mutants. Development 1994, 120, 2749–2771. [Google Scholar] [PubMed]
  187. Okano, J.; Udagawa, J.; Shiota, K. The roles of retinoic acid signaling in normal and abnormal development of the palate and tongue. Congenit. Anom. 2014, 54, 69–76. [Google Scholar] [CrossRef] [PubMed]
  188. Halilagic, A.; Ribes, V.; Ghyselinck, N.B.; Zile, M.H.; Dollé, P.; Studer, M. Retinoids control anterior and dorsal properties in the developing forebrain. Dev. Biol. 2007, 303, 362–375. [Google Scholar] [CrossRef] [PubMed]
  189. Okano, J.; Kimura, W.; Papaionnou, V.E.; Miura, N.; Yamada, G.; Shiota, K.; Sakai, Y. The regulation of endogenous retinoic acid level through cyp26b1 is required for elevation of palatal shelves. Dev. Dyn. 2012, 241, 1744–1756. [Google Scholar] [CrossRef] [PubMed]
  190. Romand, R.; Dolle, P.; Hashino, E. Retinoid signaling in inner ear development. J. Neurobiol. 2006, 66, 687–704. [Google Scholar] [CrossRef] [PubMed]
  191. Frenz, D.A.; Liu, W.; Cvekl, A.; Xie, Q.; Wassef, L.; Quadro, L.; Niederreither, K.; Maconochie, M.; Shanske, A. Retinoid signaling in inner ear development: A “goldilocks” phenomenon. Am. J. Med. Genet. A 2010, 152A, 2947–2961. [Google Scholar] [CrossRef] [PubMed]
  192. Mallo, M. Retinoic acid disturbs mouse middle ear development in a stage-dependent fashion. Dev. Biol. 1997, 184, 175–186. [Google Scholar] [CrossRef] [PubMed]
  193. Amengual, J.; Zhang, N.; Kemerer, M.; Maeda, T.; Palczewski, K.; Von Lintig, J. Stra6 is critical for cellular vitamin A uptake and homeostasis. Hum. Mol. Genet. 2014, 23, 5402–5417. [Google Scholar] [CrossRef] [PubMed]
  194. Arregi, I.; Climent, M.; Iliev, D.; Strasser, J.; Gouignard, N.; Johansson, J.K.; Singh, T.; Mazur, M.; Semb, H.; Artner, I.; et al. Retinol dehydrogenase-10 regulates pancreas organogenesis and endocrine cell differentiation via paracrine retinoic acid signalling. Endocrinology 2016. [Google Scholar] [CrossRef] [PubMed]
  195. Garnaas, M.K.; Cutting, C.C.; Meyers, A.; Kelsey, P.B., Jr.; Harris, J.M.; North, T.E.; Goessling, W. Rargb regulates organ laterality in a zebrafish model of right atrial isomerism. Dev. Biol. 2012, 372, 178–189. [Google Scholar] [CrossRef] [PubMed]
  196. Martin, M.; Gallego-Llamas, J.; Ribes, V.; Kedinger, M.; Niederreither, K.; Chambon, P.; Dolle, P.; Gradwohl, G. Dorsal pancreas agenesis in retinoic acid-deficient raldh2 mutant mice. Dev. Biol. 2005, 284, 399–411. [Google Scholar] [CrossRef] [PubMed]
  197. Niederreither, K.; Vermot, J.; Messaddeq, N.; Schuhbaur, B.; Chambon, P.; Dolle, P. Embryonic retinoic acid synthesis is essential for heart morphogenesis in the mouse. Development 2001, 128, 1019–1031. [Google Scholar] [PubMed]
  198. Lenti, E.; Farinello, D.; Yokoyama, K.K.; Penkov, D.; Castagnaro, L.; Lavorgna, G.; Wuputra, K.; Sandell, L.L.; Tjaden, N.E.; Bernassola, F.; et al. Transcription factor tlx1 controls retinoic acid signaling to ensure spleen development. J. Clin. Investig. 2016, 126, 2452–2464. [Google Scholar] [CrossRef] [PubMed]
  199. Vermot, J.; Gallego Llamas, J.; Fraulob, V.; Niederreither, K.; Chambon, P.; Dolle, P. Retinoic acid controls the bilateral symmetry of somite formation in the mouse embryo. Science 2005, 308, 563–566. [Google Scholar] [CrossRef] [PubMed]
  200. Moreno, T.A.; Kintner, C. Regulation of segmental patterning by retinoic acid signaling during Xenopus somitogenesis. Dev. Cell 2004, 6, 205–218. [Google Scholar] [CrossRef]
  201. Janesick, A.; Nguyen, T.T.; Aisaki, K.; Igarashi, K.; Kitajima, S.; Chandraratna, R.A.; Kanno, J.; Blumberg, B. Active repression by rargamma signaling is required for vertebrate axial elongation. Development 2014, 141, 2260–2270. [Google Scholar] [CrossRef] [PubMed]
  202. Mendelsohn, C.; Batourina, E.; Fung, S.; Gilbert, T.; Dodd, J. Stromal cells mediate retinoid-dependent functions essential for renal development. Development 1999, 126, 1139–1148. [Google Scholar] [PubMed]
  203. Rosselot, C.; Spraggon, L.; Chia, I.; Batourina, E.; Riccio, P.; Lu, B.; Niederreither, K.; Dolle, P.; Duester, G.; Chambon, P.; et al. Non-cell-autonomous retinoid signaling is crucial for renal development. Development 2010, 137, 283–292. [Google Scholar] [CrossRef] [PubMed]
  204. Griswold, M.D.; Hogarth, C.A.; Bowles, J.; Koopman, P. Initiating meiosis: The case for retinoic acid. Biol. Reprod. 2012, 86, 35. [Google Scholar] [CrossRef] [PubMed]
  205. Bowles, J.; Feng, C.W.; Miles, K.; Ineson, J.; Spiller, C.; Koopman, P. Aldh1a1 provides a source of meiosis-inducing retinoic acid in mouse fetal ovaries. Nat. Commun. 2016, 7, 10845. [Google Scholar] [CrossRef] [PubMed]
  206. MacLean, G.; Li, H.; Metzger, D.; Chambon, P.; Petkovich, M. Apoptotic extinction of germ cells in testes of cyp26b1 knockout mice. Endocrinology 2007, 148, 4560–4567. [Google Scholar] [CrossRef] [PubMed]
  207. Bowles, J.; Knight, D.; Smith, C.; Wilhelm, D.; Richman, J.; Mamiya, S.; Yashiro, K.; Chawengsaksophak, K.; Wilson, M.J.; Rossant, J.; et al. Retinoid signaling determines germ cell fate in mice. Science 2006, 312, 596–600. [Google Scholar] [CrossRef] [PubMed]
  208. Koubova, J.; Menke, D.B.; Zhou, Q.; Capel, B.; Griswold, M.D.; Page, D.C. Retinoic acid regulates sex-specific timing of meiotic initiation in mice. Proc. Natl. Acad. Sci. USA 2006, 103, 2474–2479. [Google Scholar] [CrossRef] [PubMed]
  209. Chanda, B.; Ditadi, A.; Iscove, N.N.; Keller, G. Retinoic acid signaling is essential for embryonic hematopoietic stem cell development. Cell 2013, 155, 215–227. [Google Scholar] [CrossRef] [PubMed]
Nutrients 08 00812 g001 550
Figure 1. Retinoid compounds differ with respect to the polar end group at the terminus of the chain. The compound all-trans-retinol (ROL) can be reversibly converted to all-trans-retinal (RAL) or to retinyl esters (RE). The carotenoid β-carotene can be converted to RAL. RAL can be irreversibly oxidized to retinoic acid (RA).
Figure 1. Retinoid compounds differ with respect to the polar end group at the terminus of the chain. The compound all-trans-retinol (ROL) can be reversibly converted to all-trans-retinal (RAL) or to retinyl esters (RE). The carotenoid β-carotene can be converted to RAL. RAL can be irreversibly oxidized to retinoic acid (RA).
Nutrients 08 00812 g001
Nutrients 08 00812 g002 550
Figure 2. Canonical RA signaling activity occurs when RA regulates gene transcription by binding as ligand to RAR nuclear transcription factors at RARE sites. (A) RARs function as heterodimer with RXRs. Binding of RA (represented by orange hexagon) to the ligand-binding domain of a RAR heterodimerized with a RXR can activate transcription; (B) RAR–RXR heterodimers bind to DNA at RARE sites. Examples of classical RARE binding sites consist of two directly repeated hexamer motifs separated by spacer nucleotide sequences of different lengths. Examples of DR5, DR2, and DR1 RAREs from important RA-regulated developmental genes are shown.
Figure 2. Canonical RA signaling activity occurs when RA regulates gene transcription by binding as ligand to RAR nuclear transcription factors at RARE sites. (A) RARs function as heterodimer with RXRs. Binding of RA (represented by orange hexagon) to the ligand-binding domain of a RAR heterodimerized with a RXR can activate transcription; (B) RAR–RXR heterodimers bind to DNA at RARE sites. Examples of classical RARE binding sites consist of two directly repeated hexamer motifs separated by spacer nucleotide sequences of different lengths. Examples of DR5, DR2, and DR1 RAREs from important RA-regulated developmental genes are shown.
Nutrients 08 00812 g002
Nutrients 08 00812 g003 550
Figure 3. RA is not present uniformly throughout an embryo, and RA signaling activity does not occur equally in all cells. The distribution of canonical ligand-dependent RA signaling in mouse embryos can be visualized by activity of a RARE-lacZ transgenic reporter [55]. (A) At embryonic day 8.5 (E8.5) RA signaling occurs predominantly in the trunk and the forebrain. RA negative tissues include the heart and most of head; (B) At E9.5 RA signaling remains strong in trunk. RA negative tissues include pharyngeal arch 1, which gives rise to the maxilla and mandible and most of the midbrain and hindbrain; (C) At E11.5 strong RA signaling activity is present in the eye, in the developing nasal region and throughout the developing spinal cord of the trunk. Forelimbs and hindlimbs are negative for RA signaling at this stage; (D) At E12.5 RA signaling is detected in the eye, in distinct regions of the trunk, and in interdigital regions of the forelimb and hindlimb. The gut, which is outside the body wall at this stage, is strongly positive for RA signal. RA-negative tissues include the tail and digits of the limb; (E) RA signaling occurs in many developing organs including the E13.5 heart. E, embryonic day; FB, forebrain; FL, forelimb; FNP, frontonasal prominence; G, gut; H, heart; HL, hindlimb; LA, left atrium; LV, left ventricle; NP, nasal prominence; PA1, pharyngeal arch 1; RA right atrium; RV, right ventricle; T, tail.
Figure 3. RA is not present uniformly throughout an embryo, and RA signaling activity does not occur equally in all cells. The distribution of canonical ligand-dependent RA signaling in mouse embryos can be visualized by activity of a RARE-lacZ transgenic reporter [55]. (A) At embryonic day 8.5 (E8.5) RA signaling occurs predominantly in the trunk and the forebrain. RA negative tissues include the heart and most of head; (B) At E9.5 RA signaling remains strong in trunk. RA negative tissues include pharyngeal arch 1, which gives rise to the maxilla and mandible and most of the midbrain and hindbrain; (C) At E11.5 strong RA signaling activity is present in the eye, in the developing nasal region and throughout the developing spinal cord of the trunk. Forelimbs and hindlimbs are negative for RA signaling at this stage; (D) At E12.5 RA signaling is detected in the eye, in distinct regions of the trunk, and in interdigital regions of the forelimb and hindlimb. The gut, which is outside the body wall at this stage, is strongly positive for RA signal. RA-negative tissues include the tail and digits of the limb; (E) RA signaling occurs in many developing organs including the E13.5 heart. E, embryonic day; FB, forebrain; FL, forelimb; FNP, frontonasal prominence; G, gut; H, heart; HL, hindlimb; LA, left atrium; LV, left ventricle; NP, nasal prominence; PA1, pharyngeal arch 1; RA right atrium; RV, right ventricle; T, tail.
Nutrients 08 00812 g003
Nutrients 08 00812 g004 550
Figure 4. RA production in embryo cells is regulated by enzymatic metabolism and catabolism. Embryo cells obtain retinoids from maternal sources via circulation. In the blood serum the hydrophobic ROL is bound by RBP4. ROL enters embryo cells predominantly through membrane diffusion. ROL can also be transported into cells via RBP4 delivery to the membrane transporter STRA6. Inside the cell hydrophobic ROL can be associated with a membrane compartment, where it can exist as free retinoid. Hydrophobic ROL can be present in the aqueous cytosol if it is bound by RBP1. ADH enzymes do not participate in metabolism of ROL in embryo tissues under normal conditions because the cytoplasmic enzymes cannot act on RBP1-bound ROL. RDH10, a membrane bound SDR, acts on free ROL, possibly from a membrane pool, or alternatively, delivered from RBP1. A related membrane SDR, DHRS3 catalyzes the reduction of RAL to ROL. RDH10 and DHRS3 are oxidoreductases that act reciprocally and enhance the activity of each other. RDH10 functions primarily as an oxidase and DHRS3 acts chiefly as a reductase, the redox directions being defined by relative abundance of cofactors NAD+ and NADPH. An alternate mechanism to generate RAL is cleavage of β-carotene by BCO1. RAL is irreversibly converted to RA by members of the ALDH1A family. Once RA is generated by oxidation of RAL, it can have several fates. RA can bind to CRABP2, which can deliver the RA into the nucleus where it can bind to RARs. RA can also be eliminated by action of CYP26 family enzymes, or it can move to neighboring cells, possibly by diffusion or transport. ER, endoplasmic reticulum; mit, mitochondrion.
Figure 4. RA production in embryo cells is regulated by enzymatic metabolism and catabolism. Embryo cells obtain retinoids from maternal sources via circulation. In the blood serum the hydrophobic ROL is bound by RBP4. ROL enters embryo cells predominantly through membrane diffusion. ROL can also be transported into cells via RBP4 delivery to the membrane transporter STRA6. Inside the cell hydrophobic ROL can be associated with a membrane compartment, where it can exist as free retinoid. Hydrophobic ROL can be present in the aqueous cytosol if it is bound by RBP1. ADH enzymes do not participate in metabolism of ROL in embryo tissues under normal conditions because the cytoplasmic enzymes cannot act on RBP1-bound ROL. RDH10, a membrane bound SDR, acts on free ROL, possibly from a membrane pool, or alternatively, delivered from RBP1. A related membrane SDR, DHRS3 catalyzes the reduction of RAL to ROL. RDH10 and DHRS3 are oxidoreductases that act reciprocally and enhance the activity of each other. RDH10 functions primarily as an oxidase and DHRS3 acts chiefly as a reductase, the redox directions being defined by relative abundance of cofactors NAD+ and NADPH. An alternate mechanism to generate RAL is cleavage of β-carotene by BCO1. RAL is irreversibly converted to RA by members of the ALDH1A family. Once RA is generated by oxidation of RAL, it can have several fates. RA can bind to CRABP2, which can deliver the RA into the nucleus where it can bind to RARs. RA can also be eliminated by action of CYP26 family enzymes, or it can move to neighboring cells, possibly by diffusion or transport. ER, endoplasmic reticulum; mit, mitochondrion.
Nutrients 08 00812 g004
Table
Table 1. Nomeclature of SDR16C enzymes RDH10 and DHRS3 from model organisms. For complete list of SDR enzymes see: www.sdr-enzymes.org.
Table 1. Nomeclature of SDR16C enzymes RDH10 and DHRS3 from model organisms. For complete list of SDR enzymes see: www.sdr-enzymes.org.
Common NameSDR FamilySDR16C Family Member IDOrganismOther Names
RDH10SDR16C4Homo sapiens
SDR16C10Mus musculus
SDR16C15Rattus norvegicus
SDR16C81Xenopus laevisrdh10b
SDR16C82Xenopus laevisrdh10a
SDR16C36Danio reriordh10-a
SDR16C37Danio reriordh10-b
DHRS3SDR16C1Homo sapiensRDH17, Rsdr1, SDR1, retSDR1
SDR16C9Mus musculusRsdr1, retSDR1
SDR16C16Rattus norvegicusrCG_31196
SDR16C83Xenopus laevis
SDR16C39Danio reriodhrs3b
SDR16C40Danio reriodhrs3a
SDR16C129Gallus gallus
Table
Table 2. Mutations or morpholino knock-down of genes involved in vitamin A metabolism and RA signaling impact development of many embryonic systems.
Table 2. Mutations or morpholino knock-down of genes involved in vitamin A metabolism and RA signaling impact development of many embryonic systems.
SystemReviewTransport, and Binding ProteinsMetabolism of ROL to RACanonical SignalingRA Elimination
RBP4, STRA6, CRABP2RHD10, DHRS3, BCO1, ALDH1A1, ALDH1A2, ALDH1A3RARα, RARβ, RARγCYP26A1, CYP26B1, CYP26C1
Anterior-posterior patterning: Brain/hindbrain[173][149][89,133,174,175,176][177,178][156,157,158,160]
Anterior-posterior patterning: axial skeleton [179,180][156,157]
Limb [89,101,175,181,182,183,184][180,185,186]
Mid-face, nasal cavity, and Palate[187][89,101,188]
* [44]
** [98]		[89,101,134,135,142][180][189]
Ear[190,191,192] [89,90,101][180]
Eye [92,93,94,193]
* [44]
** [98]		[89,101,135,142][180]
Digestive system [89][185,186]
Liver [89,101,194][195]
Lung/trachea [89,101,194]
Pancreas [194,196]
Heart [89,90,107,134,174,197][171,185,186]
Spleen [198]
Somite formation [199][200]
Posterior axis extension, tail formation [201][156,157]
Kidney/Urogenital [89][185,186,202,203][156,157]
Germ cells[204] [205] [206,207,208]
Blood cells [209]
* Compound mutation with Bco1−/−; Lrat−/− with vitamin A deficient diet; ** Compound mutant Rbp4−/−; Lrat−/− with vitamin A deficient diet.

Share and Cite

MDPI and ACS Style

Metzler, M.A.; Sandell, L.L. Enzymatic Metabolism of Vitamin A in Developing Vertebrate Embryos. Nutrients 2016, 8, 812. https://doi.org/10.3390/nu8120812

AMA Style

Metzler MA, Sandell LL. Enzymatic Metabolism of Vitamin A in Developing Vertebrate Embryos. Nutrients. 2016; 8(12):812. https://doi.org/10.3390/nu8120812

Chicago/Turabian Style

Metzler, Melissa A., and Lisa L. Sandell. 2016. "Enzymatic Metabolism of Vitamin A in Developing Vertebrate Embryos" Nutrients 8, no. 12: 812. https://doi.org/10.3390/nu8120812

APA Style

Metzler, M. A., & Sandell, L. L. (2016). Enzymatic Metabolism of Vitamin A in Developing Vertebrate Embryos. Nutrients, 8(12), 812. https://doi.org/10.3390/nu8120812

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop