Retinoic acid synthesis and functions in early embryonic development
© Kin Ting Kam et al; licensee BioMed Central Ltd. 2012
Received: 2 December 2011
Accepted: 22 March 2012
Published: 22 March 2012
Retinoic acid (RA) is a morphogen derived from retinol (vitamin A) that plays important roles in cell growth, differentiation, and organogenesis. The production of RA from retinol requires two consecutive enzymatic reactions catalyzed by different sets of dehydrogenases. The retinol is first oxidized into retinal, which is then oxidized into RA. The RA interacts with retinoic acid receptor (RAR) and retinoic acid X receptor (RXR) which then regulate the target gene expression. In this review, we have discussed the metabolism of RA and the important components of RA signaling pathway, and highlighted current understanding of the functions of RA during early embryonic development.
Keywordsretinoids retinoic acid synthesis embryonic development organogenesis
Retinoids refer to those chemicals that are structurally or functionally similar to retinol, or vitamin A , which is an essential biomolecule for embryonic development and adult body homeostasis. All retinoids retain the polyene hydrophobic tail attached to a cyclic 6-carbon ring. The polyene tail is characterized by the alternating conjugated carbon-carbon double bonds, which makes retinoids light-sensitive. In contrast with other signaling proteins, retinoids have a much lower molecular weight of approximately 300 Da. Given their molecular structures, retinoids are highly oil-soluble and able to diffuse across the cell membrane. Retinoids are involved in cellular growth, apoptosis, immune response, and epithelial growth [2–7] through the interaction with the nuclear receptors, retinoic acid receptor (RAR) and retinoid X receptor (RXR). During early embryonic development, the major active form of retinoids, all-trans retinoic acid (atRA), regulates germ layer formation, body axis formation, neurogenesis, cardiogenesis, and the development of pancreas, lung, and eye. It is also a critical element for visual function . Because of the wide spectrum of RA functions, the metabolism, regulation, and function of vitamin A have been extensively studied for decades, and here we summarize our current understanding on retinoids metabolic pathways and RA functions during early embryonic development.
2. Metabolism of vitamin A and the production of all-trans retinoic acid
Vitamin A is a necessary dietary vitamin for the normal development and vision. The critical necessity of vitamin A was hinted as early as 1881 by Nikolai Lunin, who discovered that purified protein, fat, and carbohydrate did not sustain the normal growth of mice, unless the diet was supplemented with milk. Elmer Verner McCollum, then determined in 1917 that the critical component concerned in milk was actually a "fat-soluble factor A", named in contrast to the previously discovered "water-soluble factor B", or vitamin B. These discoveries allowed Carl Edvard Bloch, a Denmark paediatrician, to identify vitamin A deficiency as the cause of night blindness, or xerophthalmia .
2.1 Conversion of Vitamin A (atROL) to all-trans retinal (atRAL)
Vitamin A (hereby referred to as all-trans retinol, atROL) is absorbed in the small intestine and esterified as retinyl esters for the blood stream transport. Retinyl ester is first transported to the liver for storage, mainly in the hepatic stellate cell. Hydrolysis of retinyl esters results in retinol, which then binds to retinol binding protein (RBP). The atROL/RBP complex is the dominant form for systematical and intercellular transport. After target organs take up the atROL/RBP complex, the atROL either is re-esterified into retinyl ester by lecithin retinol acyltransferase (LRAT) or binds to cellular retinol-binding protein (CRBP). The CRBP can prevent intracellular atROL from non-specific oxidation, immobilize intracellular retinol for storage, and acts as a carrier protein to present the atROL to respective retinol dehydrogenase for oxidation, or to LRAT for esterification . Thus, the esterification by LRAT and/or the binding to CRBP represent the most upstream regulation of atROL availability, and therefore atRA metabolism, in the cell .
Retinyl ester and CRBP-bound retinol are the main storage forms of atROL. The retinyl ester can be hydrolyzed into 11-cis retinol by isomerohydrolases [13, 14]. The cellular retinaldehyde binding protein (CRALBP) binds to 11-cis retinol with high affinity , which leads to the oxidation of 11-cis retinol to 11-cis retinal by 11-cis retinol dehydrogenase [16, 17]. The 11-cis retinal is an essential component for vision. It binds to opsin to form rhodopsin, which can absorb lights within the visible spectrum. When the 11-cis-retinal absorbs a photon, it isomerizes from the 11-cis state to atRAL. The binding of atRAL to opsin is not stable and atRAL is rapidly released from opsin. Such molecule movements cause cell membrane change, and eventually lead to generation of the nerve impulse for vision (Figure 1).
atROL/CRBP complexes are the first substrate in the metabolic pathway which leads to the production of atRA. Using atROL/CRBP as substrate, retinol dehydrogenase (RDH), which belongs to short-chain dehydrogenase/reductase (SDR) family, catalyzes the oxidation of atROL to all-trans retinal (atRAL) . This step is the rate limiting step in the production of atRA . It has also been demonstrated that in vitro free atROL can be converted into atRAL by non-specific enzymes including alcohol dehydrogenase . CRBP therefore provides a selection mechanism for specific RDH-mediated oxidation of atROL. Indeed, RDH has a much higher affinity towards atROL/CRBP complex than free atROL and the reaction depends on protein-protein interaction between RDH and CRBP . It has been demonstrated that the microsomal RDH interacts with atROL/CRBP-I in the presence of co-factor, nicotinamide adenine dinucleotide phosphate ( NADP) . Moreover, atROL/CRBP is the preferred substrate for the retinol dehydrogenase 16 (RDH16. Abbreviated as RoDH-4 in the original article), but not for 3α-hydroxysteroid dehydrogenase (3α-HSD), a similar alcohol dehydrogenase which has an even higher affinity towards free atROL . Thus, CRBP acts as a selection protein for RDH by increasing the substrate affinity for RDH, which in turn prevents non-specific oxidation of atROL by alcohol dehydrogenase.
The conversion of atROL to atRAL is, in fact, reversible. The direction - oxidation or reduction - favored by different members of SDR family depends on the substrate affinity, co-factor affinity, and the rate of reaction. In addition to CRBP that contributes to substrate affinity, another factor that contributes to substrate affinity is the intrinsic substrate binding site on the SDR family of enzymes. Retinal reductase 1 (RalR1), a human SDR, has been shown to be reactive towards both atROL and atRAL in vitro. However, RalR1 has a higher affinity and rate of reduction for atRAL than atROL, indicating that RalR1 is a retinal reductase, rather than retinol dehydrogenase, under physiological conditions . Co-factor affinity of different SDR has also been demonstrated that the co-factor favored by SDR reflects the direction of reaction catalyzed by that particular SDR (reviewed by Pares) .
Apart from RalR1, a number of retinal reductases have been identified in the past decades. A human short-chained retinol reductase (retSDR1) identified in a neuroblastoma cell line has been shown to promote the formation of retinyl ester in the presence of exogenous atRAL . A mouse liver peroxisomal SDR termed mouse retinal reductase (RRD) also showed a high atRAL-specific reductase activity in the presence of CRBP in vitro. This enzyme was induced by peroxisome proliferator-activated receptor (PPAR), suggesting a relationship between retinoid metabolism and peroxisome activity . Using in vitro assay, some studies have identified reductases which showed in vitro retinal-reducing activity. For example, human aldose reductase and human small intestine aldose reductase can function as retinal reductase in vitro. Similarly, the mouse short-chained aldehyde reductase (SCALD) could reduce atRAL and 9-cis retinal in vitro. However, these studies are based on in vitro biochemical analysis only and do not take into account the substrate selection by CRBP. Therefore, the enzymatic activities on different retinal reported should not be taken as a direct evidence for physiological retinal reductases.
2.2 Conversion of atRAL to atRA
Similar to atROL, all-trans retinal is also transported by CRBP in the cell, and is then oxidized to atRA. The oxidation from atRAL to atRA has been observed as early as 1960 . The oxidation of atRAL to atRA was mediated by various retinaldehyde dehydrogenases (RALDH). At least 3 RALDHs have been identified in human, mouse, and Xenopus, with different physiological functions . Retinaldehyde dehydrogenase 1 (Raldh1) is highly expressed in the dorsal retina of mouse embryos , in epithelial tissues of adult mice and Xenopus, and in the stomach and small intestine of adult rats . Xenopus raldh1 has been shown to be an atRA synthesizing enzyme in a retinoic acid responsive cell line . RALDH1 -/- mice also suggest that Raldh1 is capable of atRA synthesis . However, knockout of RALDH1 did not severely affect the morphology of the retina although RALDH1 is localized in the dorsal retina , indicating that other enzymes might redundantly share the function of RALDH1.
The retinaldehyde dehydrogenase 2 (RALDH2) was identified in human, mouse, chick, zebrafish and Xenopus[37–39]. Interestingly, RALDH2 was identified as a crucial enzyme for atRA synthesis in different organisms. Knockout of RALDH2 was embryonic lethal during the post-implantation period in mice , suggesting that atRA is essential for normal embryonic development. The phenotypes of RALDH2 knock-out mice include severely impaired segmentation of rhombomeres, altered homeobox gene expression pattern, and defective neural crest cell migration . In zebrafish, knockdown of raldh2 caused a down-regulation of retinoic acid signaling, malformation in the central nervous system, and disruption of left-right asymmetry [42, 43]. The raldh2 mutant, neckless (nls), displayed a suppressed formation of the midbrain to hindbrain region, as well as segmentation defects in rhombomeres . Such defects were attributed to the reduction in atRA signaling , since the spatial and temporal pattern of atRA signaling is maintained mainly by raldh2 and a degradative enzyme cytochrome P450 hydroxylase A1 (cyp26a1) in zebrafish. In Xenopus embryos, ectopic expression of raldh2 caused teratogenic effects such as the expression of posterior neural markers (en2 and krox20) in the anterior region, which is similar to that due to atRA toxicity , suggesting that raldh2 is an important enzyme in maintaining atRA homeostasis in embryos. Knockdown of raldh2 in Xenopus embryos caused a shortening of anteroposterior axis and a posterior shift of neural marker en2 and krox20. Collectively, such evidence indicated that raldh2 plays a crucial role in the anteroposterior patterning of the central nervous system and trunk axis through regulation of the RA signaling.
Retinaldehyde dehydrogenase 3 (RALDH3) has been identified in human, chick, mouse, zebrafish, and Xenopus, and is expressed in the ventral retina across various species [47–51]. Studies in mouse have shown that RALDH3 was mainly involved in the frontonasal development and patterning of ocular structures . Mice lacking RALDH3 were neonatal lethal, due to the respiratory tract obstruction in nasal region, and the neonatal lethality could be rescued by atRA supplements , suggesting that RALDH3 is an atRA synthesis enzyme. In 2007, Halilagic et al. showed that atRA production by RALDH3 contributed to the correct patterning of the anterior and dorsal boundaries of the developing forebrain . It was further delineated that RALDH3 knockout mice exhibited loss of dopamine receptor D2 in the ventral forebrain. These studies suggest that RALDH3 is essential for the development of the central nervous system and the morphogenesis of anterior head structures .
2.3 Degradation of atRA
All-trans retinoic acid is degraded by CYP26 enzymes, which belong to cytochrome P450 hydroxylase family. A number of CYP26 family including CYP26A1, B1, C1, and D1 have been characterized and all of them possess the ability to degrade atRA into less bio-active retinoid [61–63]. Rhombomeric alteration defects were only observed by the knockdown of all three cyp26 enzymes in zebrafish , suggesting that cyp26a1, b1 and c1 act redundantly in hindbrain patterning. CYP26A1 is induced by atRA while it promotes the hydroxylation of atRA into 4-hydroxy retinoic acid, 4-oxo retinoic acid, and 18-hyroxy retinoic acid [45, 65–67]. Since RALDH2 and CYP26A1 are both regulated by atRA itself, the metabolism of atRA therefore forms an auto-regulatory loop that regulates and balances atRA levels in embryos. Such regulation not only maintains the endogenous atRA level within a normal range, but also allows the organisms to respond to exogenous atRA fluctuation.
3. Retinoic acid receptors
atRA is carried into the nucleus by CRABP-II, and interacts with RARs, which themselves are transcription factors. RARs belong to retinoid receptor family, which also includes another group called retinoid X receptors (RXRs). RARs recognize both atRA and 9-cis retinoic acid, while RXRs only recognize 9-cis retinoic acid. Upon the ligand binding, RAR dimerizes with RXR to form a heterodimer, which then initiate gene transcription by binding to the retinoic acid response element (RARE) in the promoter region of the targets genes (Figure 2). The RAR family consists of RARα/β/γ three members that bind to atRA [68–71]. Single knockout mice that lack each of RARs were not embryonic lethal and did not display the complete spectrum of vitamin A deficiency phenotype. A disruption in RARα did not cause any observable phenotypic change in a mouse model . Knockout of RARβ caused a reduction in the body weight and ocular defect, while limb formation remained normal . Double knockout of two RARγ subtypes caused growth deficiency, cartilage dysmorphogenesis, and vertebrate malformation . These results imply that RARs work redundantly and compensate the function of each other. Indeed, knockdown of RARα caused an increase in the expression level of RARβ and RARγ . Only double knockout mutants showed phenotype close to the symptoms of vitamin A deficiency . The auto-regulatory loop of RAR expression is similar to that regulating the expression of of RALDH2 and CYP26a1. Moreover, RARE has been identified in the promoter regions of RARα and β[77–79], indicating that the expression of these RARs is also under control of atRA.
Similarly, there are also three subtypes of RXRs . RXRα knockout mice were embryonic lethal, potentially due to malformation of the heart in utero . RXRβ knockout mice were 50% embryonic lethal, and the surviving littermates were morphologically normal except spermatogenesis defects which rendered the male sterile , while the RXRγ-null mutant mice were morphologically normal when compared with the wild type . Moreover, the mice carrying only one copy of RXRα (RXRα+/-/RXRβ-/-/RXRγ-/-) were viable, suggesting one copy of RXRα is sufficient to carry out most of function of the RXRs . Since atRA-bound RAR can form heterodimer with RXR in the absence of 9-cis retinoic acid and is still active in transcription activities, the importance of RXRs may not be as critical as RARs. This may explain why only one copy of RXRα is sufficient for the mouse embryonic development. Taken together, these results suggest that each of the RAR subtypes function redundantly and most of the RXR subtypes are not critical for the embryonic development.
While RARs mainly mediate the RA signaling, it has been revealed by many studies that ligand-bound RXRs activate other signaling pathways by forming heterodimer with other nuclear receptors such as liver X receptor (LXR), farnesoid X receptor (FXR), and PPAR [84–86] (Figure 2). LXR mainly functions as a sensor of cholesterol levels by recognizing its ligand oxysterols. Overloading cells with cholesterol activates LXR/RXR heterodimers which in turn initiate transcription of target genes, thereby regulate cholesterol transport, uptake, metabolism, and bile acid synthesis in the liver [87, 88]. FXR can recognize free or conjugated bile acid and thus acts as an intracellular sensor of bile acid to regulate the metabolism of bile acid in the liver. Activation of liganded-FXR/RXR promotes bile acid efflux and inhibits bile acid synthesis . PPAR is a lipid sensing nuclear receptor, recognizing a wide range of fatty acids . These interactions between LXR, FXR, PPAR, and RXR reflect the complexity of RXR functions and their potentials on the RA signaling. In addition, not only do RXRs take part promiscuously in multiple signaling pathways, the expression of these nuclear receptors is also under control of complex feedback loops and cross-talks with other signaling pathways . The heterodimerization of RXR with RAR, LXR, FXR, or PPAR is therefore mutually competitive, and atRA signaling not only triggers the transcription of its target genes, but also competitively suppresses the transcription of others. This may explain the board spectrum of atRA-induced teratogenicity observed in embryos.
4. Differential expression and gene regulation of RA metabolic enzymes
5. Retinoic acid signaling during early embryonic development
The RA signaling pathway has been implicated in various developmental processes. During early embryonic development, retinoids act as an important morphogen across different species from invertebrate to metazoan including human [97, 98]. It participates in regulating various biological processes, such as apoptosis and differentiation, and cell fate specification.
5.1 Axis formation
The RA signaling has been implicated in embryonic axis formation as well. Evidence shows that it interacts with Nodal signaling to regulate dorsoventral axis formation. The mice embryos lacking all three Cyp26 genes displayed secondary body axes due to expansion of the Nodal expression domain. In fact, the mouse Nodal gene contains an RARE in the intron 1 that is highly conserved among mammals . Moreover, pre-gastrulation mouse embryos express Cyp26 s but not Raldh s suggesting that maternal RA is decreased by embryonic Cyp26s for proper Nodal expression during embryonic patterning .
In addition to the dorsoventral axis formation, cyp26 is also important for restricting the expression of posterior genes during the anteroposterior patterning . Experiments in zebrafish embryos indicate that reduction of atRA by ectopic cyp26 decreased the expression of posterior genes meis3. Consistent with this, knockdown of cyp26 led to the anterior expansion of meis3. Interestingly, the expression of cyp26 is suppressed by the FGF and Wnt signalings, which are involved in the specification of posterior trunk during the gastrulation. Thus, RA together with FGF and Wnt signalings forms a complex regulatory network to regulate the anteroposterior axis formation in gastrula embryos, the cyp26 being one of the cross-talk genes linking these signaling pathways .
The RALDHs and CYP26s enzymes also participate in the anteroposterior patterning of the central nervous system by maintaining a gradient of atRA along the axis . Global application of atRA to mouse embryos during day 7 of gestation caused severe head deformations, such as exencephaly, microcephaly, and anencephaly, whereas exposure of embryos to atRA during day 8 of gestation led to severe caudal truncations reminiscent of the human caudal regression syndrome [102, 103]. Similar phenomena were observed with Xenopus embryos as well [104–106].
Vertebrates display asymmetric placement of various internal organs including the heart, liver, spleen, and gut, and the asymmetric development of paired organs such as brain hemispheres and lungs. Treatment with RA antagonist in mouse led to randomization of heart looping and perturbed sideness of node . Application of RA antagonist revealed that the RA signaling sequentially controlled visceral and heart laterality . On the other hand, the somites obviously avoid the influence of signaling pathways that regulate the left-right asymmetry. The somites, derived from the trunk paraxial mesoderm and sequentially segmented along the anteroposterior axis, are formed as bilaterally paired units. However, the mice embryos that lack Raldh2 exhibited asymmetric somite formation , which was due to left-right desynchronization of the segmentation clock oscillations. Such defects were also observed in RA deficient chick  and zebrafish . It is therefore postulated that the RA form a protection zone, protecting the somite from the left-right asymmetric signals to maintain the bilateral symmetry of somites columns.
5.2 Neural differentiation
atRA has been known for its ability to induce neural differentiation. During neural differentiation in early embryonic development, the pro-neural induction factor Neurogenin 2 (Neurog2) is required for primary sensory neuron specification . Two RARE identified in the promoter region of mouse Neurog2 provide evidence that atRA directly regulates the expression of Neurog2 and therefore neural differentiation . In addition, it has been shown that atRA treatment can induce pluripotent embryonic carcinoma stem cell line NT2 cells to differentiate into forebrain, hindbrain, and spinal cord neural progenitors , and the NT2 cells displayed GABAergic and glutamatergic phenotype. In line with this, mouse embryonic stem cells could be induced into GABAergic neurons by atRA treatment in vitro. These in vitro findings were also supported by an in vivo study that knockdown of RARα abolished the effect of atRA on dendritic growth . Collectively, these studies support the view that atRA is required for neural differentiation in the central nervous system.
5.3 Hindbrain patterning
In addition, in vitro data have also demonstrated a role of RA in pancreas development. In a defined in vitro explant system, RA treatment of cultured mouse E10.5 dorsal pancreatic buds could induce the generation of Ngn3+ endocrine progenitor cells and stimulate their further differentiation into β-cells by activating a differentiation program that recapitulates the normal temporal program of β-cell differentiation . In zebrafish, exogenous RA led to expansion of both exo- and endocrine cells, while in Xenopus embryos as well as cultured mouse embryonic pancreatic rudiments, exogenous RA led to an expansion of the endocrine cell population at the expense of the exocrine cells in the dorsal pancreas [129, 141, 142]. Similarly, the induction of pancreatic fate by RA in endodermalized naive ectoderm dissected from early Xenopus gastrulae only showed the generation of early insulin-expressing cells [143, 144]. Therefore, cautions should be taken to apply RA at the right time and the right dose (close to physiological concentration in early embryos) for in vitro induction of mature pancreatic β-cells from embryonic stem cells.
The effect of RA on cardiogenesis was first demonstrated in quail that vitamin A deficiency could induce defective primitive heart development . Further evidence shows that RA signaling is required for the formation of cardiac progenitors , and the correct modeling of the early heart field and the anteroposterior patterning of the heart is controlled by atRA through the action of Isl1 and Fgf8 signaling pathway [147, 148]. Knockout mice embryos lacking Raldh2 showed an abnormal development of the second heart field (SHF) , which is a population of undifferentiated cardiac precursor cells originating from the pharyngeal mesoderm and lying medial to the cardiac crescent (the first heart field). The expression of SHF markers including Isl1, Tbx1, and Fgf8, was posteriorly expanded in these embryos , indicating that the RA signaling is required for the restriction of SHF. Defects in the formation of a proper heart tube might also partially explain why Raldh2-/- is embryonic lethal . Studies in zebrafish indicated RA functions in the restriction of cardiac specification . During this process, if RA signaling was inhibited in lateral mesoderm, the uncommitted cells could differentiate into myocardial progenitor cells instead of pharyngeal or pancreatic cells , leading to the expansion of cardiomyocytes.
In addition to the heart development, the RA signaling has also been implicated in heart regeneration in adult zebrafish. Gene profiling assay indicated that raldh2 was one of the most highly induced genes in the regenerating heart . After the ventricular injury, raldh2 was activated in the endocardium, but its expression was subsequently restricted in endocardial cells at the injury site one day post-trauma as the repairing cardiogenesis began. By 7 days after amputation, the epicardial cells at the injury site also expressed raldh2. Inhibition of RARs or expression of an RA-degrading enzyme blocked regenerative cardiomyocyte proliferation . These findings reveal essential roles of RA in repairing the damaged heart tissue and promoting cardiomyocyte proliferation.
There is increasing evidence indicating that atRA plays important roles in kidney development [153–155]. The kidney field is derived from the intermediate mesoderm. The specification of renal progenitor cells is influenced by RA signals emanating from the paraxial mesoderm [153–155]. Recent studies in Xenopus and zebrafish have demonstrated that ectopic production of RA increased the size of the kidney field, while blocking the pathway inhibited the kidney specification [86, 154]. In Xenopus, pax8 and lhx1, which are the earliest determinants of pronephric fate are both under control of the RA signaling [154, 156], while pteg, an early pronephric marker, is a direct target of the RA signaling and an essential factor for pronephric specification . Another critical factor for the pronephros development, Wilm's tumor suppressor (wt1), is under direct control of the RA signaling as well [158, 159]. Inhibition of RA by BMS453 treatment caused reduction of pronephros field, as revealed by the decreased expression of the pronephros markers including smp-30 and pax2 at the late tailbud stage . Furthermore, in Xenopus embryos, the pluripotent animal cap cells treated with RA and activin could differentiate into pronephros tissue [154, 160]. Likewise, the RA signaling is also essential for directing the proximodistal patterning of pronephric nephron in zebrafish . The exogenous RA could induce proximal segment fates at the expense of distal fates, whereas inhibition of the RA signaling caused a loss of the proximal segments and an expansion of the distal segments.
Interestingly, inactivation of both RARα and RARβ in mice embryos resulted in renal malformations . Further evidence showed that RARα and RARβ were co-expressed with Ret, a receptor tyrosine kinase involved in renal development, in renal stromal mesenchyme, where their deletion led to altered stromal cell patterning, impaired ureteric bud growth, and down-regulation of Ret in the ureteric bud. Moreover, studies in mice indicate that the RA signaling in ureteric bud cells mainly depends on atRA generated through Raldh2 in stromal cells .
Evidence indicates that disruption of the RA signaling during early development caused abnormalities of lung formation. Either knockout of Raldh2 or treatment with BMS 493, a RA inhibitor, caused defects of lung formation in mice . During primary lung bud morphogenesis, although RA is not required for specification of lung cell fate in the endoderm, it is essential for the induction of the primordial lung buds [163, 164]. During the induction of lung bud, the RA signaling inhibits the expression of Dkk-1, the Wnt signaling inhibitor, in the foregut mesoderm. This inhibition in turn activates Wnt signaling in the lung bud region. At the same time, the RA signaling also inhibits TGF-β signaling. The balanced Wnt and TGF-β signalings coordinate with each other to induce and maintain the optimal expression level of Fgf10 for the induction of the lung primordium . Furthermore, airway branching was accompanied by down-regulation of the RA signaling pathway , thus regional mechanisms that control RA availability and utilization are important for the lung morphogenesis.
To date, it has been demonstrated that the RA signaling plays sophisticated roles in early embryonic development. In fact, gastrulation is a very critical period for the RA signaling to exert its function in the regionalization of all three germ layers along the anteroposterior axis. RA is mainly generated in the mesoderm and thus can be most efficiently used. It is not clear as to how the RA metabolic enzymes coordinate with each other to generate the RA gradient at right time, right region, and with right strength during early embryonic development. Future studies are needed to identify the immediate and direct RA target genes in distinct RA responsive cells and to define the crosstalks between RA and other signaling pathways, such as hedgehog, FGF, Wnt, and Notch signalings for the formation and regionalization of three germ layers. Such knowledge will be essential for understanding organogenesis and establishing reliable strategies for stem cell differentiation into specific cell types that can be used for treatment of human diseases.
We thank members of our laboratories for valuable discussion. This work is supported by GRF grant from the Research Grants Council of Hong Kong (No. CUHK480709) to HZ, the National Basic Research Program of China (2009CB941202), and the fund from the Key Project of Knowledge Innovation Program of the Chinese Academy of Sciences (KSCX2-YW-R-083) to YLC. RKTK was supported by the Graduate Studentships from The Chinese University of Hong Kong.
- Tang XH, Gudas LJ: Retinoids, retinoic acid receptors, and cancer. Annu Rev Pathol. 2011, 6: 345-364. 10.1146/annurev-pathol-011110-130303PubMedView ArticleGoogle Scholar
- Duriancik DM, Lackey DE, Hoag KA: Vitamin A as a regulator of antigen presenting cells. J Nutr. 140 (8): 1395-1399.Google Scholar
- Gudas LJ, Wagner JA: Retinoids regulate stem cell differentiation. J Cell Physiol. 226 (2): 322-330.Google Scholar
- Hogarth CA, Griswold MD: The key role of vitamin A in spermatogenesis. J Clin Invest. 120 (4): 956-962.Google Scholar
- Mora JR, Iwata M, von Andrian UH: Vitamin effects on the immune system: vitamins A and D take centre stage. Nat Rev Immunol. 2008, 8 (9): 685-698. 10.1038/nri2378PubMed CentralPubMedView ArticleGoogle Scholar
- Mukherjee S, Date A, Patravale V, Korting HC, Roeder A, Weindl G: Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety. Clin Interv Aging. 2006, 1 (4): 327-348. 10.2147/ciia.2006.1.4.327PubMed CentralPubMedView ArticleGoogle Scholar
- Pino-Lagos K, Benson MJ, Noelle RJ: Retinoic acid in the immune system. Ann N Y Acad Sci. 2008, 1143: 170-187. 10.1196/annals.1443.017PubMedView ArticleGoogle Scholar
- Davies WL, Hankins MW, Foster RG: Vertebrate ancient opsin and melanopsin: divergent irradiance detectors. Photochem Photobiol Sci. 2010, 9 (11): 1444-1457. 10.1039/c0pp00203hPubMedView ArticleGoogle Scholar
- Wolf G: The discovery of the visual function of vitamin A. J Nutr. 2001, 131 (6): 1647-1650.PubMedGoogle Scholar
- D'Ambrosio DN, Clugston RD, Blaner WS: Vitamin A Metabolism: An Update. 2011, 3 (1): 63-103.Google Scholar
- Penzes P, Napoli JL: Holo-cellular retinol-binding protein: distinction of ligand-binding affinity from efficiency as substrate in retinal biosynthesis. Biochemistry. 1999, 38 (7): 2088-2093. 10.1021/bi982228tPubMedView ArticleGoogle Scholar
- Liu L, Gudas LJ: Disruption of the lecithin:retinol acyltransferase gene makes mice more susceptible to vitamin A deficiency. J Biol Chem. 2005, 280 (48): 40226-40234. 10.1074/jbc.M509643200PubMedView ArticleGoogle Scholar
- Deigner PS, Law WC, Canada FJ, Rando RR: Membranes as the energy source in the endergonic transformation of vitamin A to 11-cis-retinol. Science. 1989, 244 (4907): 968-971. 10.1126/science.2727688PubMedView ArticleGoogle Scholar
- Mata NL, Moghrabi WN, Lee JS, Bui TV, Radu RA, Horwitz J, Travis GH: Rpe65 is a retinyl ester binding protein that presents insoluble substrate to the isomerase in retinal pigment epithelial cells. J Biol Chem. 2004, 279 (1): 635-643.PubMedView ArticleGoogle Scholar
- Saari JC, Nawrot M, Kennedy BN, Garwin GG, Hurley JB, Huang J, Possin DE, Crabb JW: Visual cycle impairment in cellular retinaldehyde binding protein (CRALBP) knockout mice results in delayed dark adaptation. Neuron. 2001, 29 (3): 739-748. 10.1016/S0896-6273(01)00248-3PubMedView ArticleGoogle Scholar
- Driessen CA, Janssen BP, Winkens HJ, van Vugt AH, de Leeuw TL, Janssen JJ: Cloning and expression of a cDNA encoding bovine retinal pigment epithelial 11-cis retinol dehydrogenase. Invest Ophthalmol Vis Sci. 1995, 36 (10): 1988-1996.PubMedGoogle Scholar
- Simon A, Hellman U, Wernstedt C, Eriksson U: The retinal pigment epithelial-specific 11-cis retinol dehydrogenase belongs to the family of short chain alcohol dehydrogenases. J Biol Chem. 1995, 270 (3): 1107-1112. 10.1074/jbc.270.3.1107PubMedView ArticleGoogle Scholar
- Duester G: Families of retinoid dehydrogenases regulating vitamin A function: production of visual pigment and retinoic acid. Eur J Biochem. 2000, 267 (14): 4315-4324. 10.1046/j.1432-1327.2000.01497.xPubMedView ArticleGoogle Scholar
- Agadir A, Nau H, Blaner WS: Retinoids: the biochemical and molecular basis of Vitamin A and retinoid action. 1999, Berlin; New York Springer.Google Scholar
- Posch KC, Enright WJ, Napoli JL: Retinoic acid synthesis by cytosol from the alcohol dehydrogenase negative deermouse. Arch Biochem Biophys. 1989, 274 (1): 171-178. 10.1016/0003-9861(89)90428-1PubMedView ArticleGoogle Scholar
- Noy N: Retinoid-binding proteins: mediators of retinoid action. Biochem J. 2000, 348 (Pt 3): 481-495.PubMed CentralPubMedView ArticleGoogle Scholar
- Boerman MH, Napoli JL: Characterization of a microsomal retinol dehydrogenase: a short-chain alcohol dehydrogenase with integral and peripheral membrane forms that interacts with holo-CRBP (type I). Biochemistry. 1995, 34 (21): 7027-7037. 10.1021/bi00021a014PubMedView ArticleGoogle Scholar
- Lapshina EA, Belyaeva OV, Chumakova OV, Kedishvili NY: Differential recognition of the free versus bound retinol by human microsomal retinol/sterol dehydrogenases: characterization of the holo-CRBP dehydrogenase activity of RoDH-4. Biochemistry. 2003, 42 (3): 776-784. 10.1021/bi026836rPubMedView ArticleGoogle Scholar
- Belyaeva OV, Stetsenko AV, Nelson P, Kedishvili NY: Properties of short-chain dehydrogenase/reductase RalR1: characterization of purified enzyme, its orientation in the microsomal membrane, and distribution in human tissues and cell lines. Biochemistry. 2003, 42 (50): 14838-14845. 10.1021/bi035288uPubMedView ArticleGoogle Scholar
- Pares X, Farres J, Kedishvili N, Duester G: Medium- and short-chain dehydrogenase/reductase gene and protein families: Medium-chain and short-chain dehydrogenases/reductases in retinoid metabolism. Cell Mol Life Sci. 2008, 65 (24): 3936-3949. 10.1007/s00018-008-8591-3PubMed CentralPubMedView ArticleGoogle Scholar
- Cerignoli F, Guo X, Cardinali B, Rinaldi C, Casaletto J, Frati L, Screpanti I, Gudas LJ, Gulino A, Thiele CJ: retSDR1, a short-chain retinol dehydrogenase/reductase, is retinoic acid-inducible and frequently deleted in human neuroblastoma cell lines. Cancer Res. 2002, 62 (4): 1196-1204.PubMedGoogle Scholar
- Lei Z, Chen W, Zhang M, Napoli JL: Reduction of all-trans-retinal in the mouse liver peroxisome fraction by the short-chain dehydrogenase/reductase RRD: induction by the PPAR alpha ligand clofibrate. Biochemistry. 2003, 42 (14): 4190-4196. 10.1021/bi026948iPubMedView ArticleGoogle Scholar
- Crosas B, Hyndman DJ, Gallego O, Martras S, Pares X, Flynn TG, Farres J: Human aldose reductase and human small intestine aldose reductase are efficient retinal reductases: consequences for retinoid metabolism. Biochem J. 2003, 373 (Pt 3): 973-979.PubMed CentralPubMedView ArticleGoogle Scholar
- Kasus-Jacobi A, Ou J, Bashmakov YK, Shelton JM, Richardson JA, Goldstein JL, Brown MS: Characterization of mouse short-chain aldehyde reductase (SCALD), an enzyme regulated by sterol regulatory element-binding proteins. J Biol Chem. 2003, 278 (34): 32380-32389. 10.1074/jbc.M304969200PubMedView ArticleGoogle Scholar
- Dowling JE, Wald G: The role of vitamin A acid. Vitam Horm. 1960, 18: 515-541.PubMedView ArticleGoogle Scholar
- Duester G, Mic FA, Molotkov A: Cytosolic retinoid dehydrogenases govern ubiquitous metabolism of retinol to retinaldehyde followed by tissue-specific metabolism to retinoic acid. Chem Biol Interact. 2003, 143-144: 201-210.PubMedView ArticleGoogle Scholar
- Haselbeck RJ, Hoffmann I, Duester G: Distinct functions for Aldh1 and Raldh2 in the control of ligand production for embryonic retinoid signaling pathways. Dev Genet. 1999, 25 (4): 353-364. 10.1002/(SICI)1520-6408(1999)25:4<353::AID-DVG9>3.0.CO;2-GPubMed CentralPubMedView ArticleGoogle Scholar
- Ang HL, Duester G: Retinoic acid biosynthetic enzyme ALDH1 localizes in a subset of retinoid-dependent tissues during xenopus development. Dev Dyn. 1999, 215 (3): 264-272. 10.1002/(SICI)1097-0177(199907)215:3<264::AID-AJA8>3.0.CO;2-IPubMedView ArticleGoogle Scholar
- Frota-Ruchon A, Marcinkiewicz M, Bhat PV: Localization of retinal dehydrogenase type 1 in the stomach and intestine. Cell Tissue Res. 2000, 302 (3): 397-400. 10.1007/s004410000281PubMedView ArticleGoogle Scholar
- Ang HL, Duester G: Stimulation of premature retinoic acid synthesis in Xenopus embryos following premature expression of aldehyde dehydrogenase ALDH1. Eur J Biochem. 1999, 260 (1): 227-234. 10.1046/j.1432-1327.1999.00139.xPubMedView ArticleGoogle Scholar
- Fan X, Molotkov A, Manabe S, Donmoyer CM, Deltour L, Foglio MH, Cuenca AE, Blaner WS, Lipton SA, Duester G: Targeted disruption of Aldh1a1 (Raldh1) provides evidence for a complex mechanism of retinoic acid synthesis in the developing retina. Mol Cell Biol. 2003, 23 (13): 4637-4648. 10.1128/MCB.23.13.4637-4648.2003PubMed CentralPubMedView ArticleGoogle Scholar
- Blentic A, Gale E, Maden M: Retinoic acid signalling centres in the avian embryo identified by sites of expression of synthesising and catabolising enzymes. Dev Dyn. 2003, 227 (1): 114-127. 10.1002/dvdy.10292PubMedView ArticleGoogle Scholar
- Chen Y, Pollet N, Niehrs C, Pieler T: Increased XRALDH2 activity has a posteriorizing effect on the central nervous system of Xenopus embryos. Mech Dev. 2001, 101 (1-2): 91-103. 10.1016/S0925-4773(00)00558-XPubMedView ArticleGoogle Scholar
- Niederreither K, McCaffery P, Drager UC, 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 (1): 67-78. 10.1016/S0925-4773(96)00653-3PubMedView ArticleGoogle Scholar
- Niederreither K, Subbarayan V, Dolle P, Chambon P: Embryonic retinoic acid synthesis is essential for early mouse post-implantation development. Nat Genet. 1999, 21 (4): 444-448. 10.1038/7788PubMedView ArticleGoogle Scholar
- Niederreither K, Vermot J, Schuhbaur B, Chambon P, Dolle P: Retinoic acid synthesis and hindbrain patterning in the mouse embryo. Development. 2000, 127 (1): 75-85.PubMedGoogle Scholar
- Grandel H, Lun K, Rauch GJ, Rhinn M, Piotrowski T, Houart C, Sordino P, Kuchler AM, Schulte-Merker S, Geisler R: 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 (12): 2851-2865.PubMedGoogle Scholar
- Kawakami Y, Raya A, Raya RM, Rodriguez-Esteban C, Belmonte JC: Retinoic acid signalling links left-right asymmetric patterning and bilaterally symmetric somitogenesis in the zebrafish embryo. Nature. 2005, 435 (7039): 165-171. 10.1038/nature03512PubMedView ArticleGoogle Scholar
- Begemann G, Marx M, Mebus K, Meyer A, Bastmeyer M: Beyond the neckless phenotype: influence of reduced retinoic acid signaling on motor neuron development in the zebrafish hindbrain. Dev Biol. 2004, 271 (1): 119-129. 10.1016/j.ydbio.2004.03.033PubMedView ArticleGoogle Scholar
- Dobbs-McAuliffe B, Zhao Q, Linney E: Feedback mechanisms regulate retinoic acid production and degradation in the zebrafish embryo. Mech Dev. 2004, 121 (4): 339-350. 10.1016/j.mod.2004.02.008PubMedView ArticleGoogle Scholar
- Strate I, Min TH, Iliev D, Pera EM: Retinol dehydrogenase 10 is a feedback regulator of retinoic acid signalling during axis formation and patterning of the central nervous system. Development. 2009, 136 (3): 461-472. 10.1242/dev.024901PubMedView ArticleGoogle Scholar
- Koenig SF, Brentle S, Hamdi K, Fichtner D, Wedlich D, Gradl D: En2, Pax2/5 and Tcf-4 transcription factors cooperate in patterning the Xenopus brain. Dev Biol. 340 (2): 318-328.Google Scholar
- Lupo G, Liu Y, Qiu R, Chandraratna RA, Barsacchi G, He RQ, Harris WA: Dorsoventral patterning of the Xenopus eye: a collaboration of Retinoid, Hedgehog and FGF receptor signaling. Development. 2005, 132 (7): 1737-1748. 10.1242/dev.01726PubMedView ArticleGoogle Scholar
- Mic FA, Molotkov A, Fan X, Cuenca AE, Duester G: RALDH3, a retinaldehyde dehydrogenase that generates retinoic acid, is expressed in the ventral retina, otic vesicle and olfactory pit during mouse development. Mech Dev. 2000, 97 (1-2): 227-230. 10.1016/S0925-4773(00)00434-2PubMedView ArticleGoogle Scholar
- Pittlik S, Domingues S, Meyer A, Begemann G: Expression of zebrafish aldh1a3 (raldh3) and absence of aldh1a1 in teleosts. Gene Expr Patterns. 2008, 8 (3): 141-147. 10.1016/j.gep.2007.11.003PubMedView ArticleGoogle Scholar
- Suzuki R, Shintani T, Sakuta H, Kato A, Ohkawara T, Osumi N, Noda M: Identification of RALDH-3, a novel retinaldehyde dehydrogenase, expressed in the ventral region of the retina. Mech Dev. 2000, 98 (1-2): 37-50. 10.1016/S0925-4773(00)00450-0PubMedView ArticleGoogle Scholar
- Molotkova N, Molotkov A, Duester G: Role of retinoic acid during forebrain development begins late when Raldh3 generates retinoic acid in the ventral subventricular zone. Dev Biol. 2007, 303 (2): 601-610. 10.1016/j.ydbio.2006.11.035PubMed CentralPubMedView ArticleGoogle Scholar
- Dupe V, Matt N, Garnier JM, Chambon P, Mark M, Ghyselinck NB: 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 (24): 14036-14041. 10.1073/pnas.2336223100PubMed CentralPubMedView ArticleGoogle Scholar
- Halilagic A, Ribes V, Ghyselinck NB, Zile MH, Dolle P, Studer M: Retinoids control anterior and dorsal properties in the developing forebrain. Dev Biol. 2007, 303 (1): 362-375. 10.1016/j.ydbio.2006.11.021PubMedView ArticleGoogle Scholar
- Chytil F, Ong DE: Cellular retinol- and retinoic acid-binding proteins in vitamin A action. Fed Proc. 1979, 38 (11): 2510-2514.PubMedGoogle Scholar
- Napoli JL, Boerman MH, Chai X, Zhai Y, Fiorella PD: Enzymes and binding proteins affecting retinoic acid concentrations. J Steroid Biochem Mol Biol. 1995, 53 (1-6): 497-502. 10.1016/0960-0760(95)00096-IPubMedView ArticleGoogle Scholar
- Hoegberg P, Schmidt CK, Fletcher N, Nilsson CB, Trossvik C, Gerlienke Schuur A, Brouwer A, Nau H, Ghyselinck NB, Chambon P: Retinoid status and responsiveness to 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) in mice lacking retinoid binding protein or retinoid receptor forms. Chem Biol Interact. 2005, 156 (1): 25-39. 10.1016/j.cbi.2005.06.006PubMedView ArticleGoogle Scholar
- Sessler RJ, Noy N: A ligand-activated nuclear localization signal in cellular retinoic acid binding protein-II. Mol Cell. 2005, 18 (3): 343-353. 10.1016/j.molcel.2005.03.026PubMedView ArticleGoogle Scholar
- Stachurska E, Loboda A, Niderla-Bielinska J, Szperl M, Juszynski M, Jozkowicz A, Dulak J, Ratajska A: Expression of cellular retinoic acid-binding protein I and II (CRABP I and II) in embryonic mouse hearts treated with retinoic acid. Acta Biochim Pol. 58 (1): 19-29.PubMedGoogle Scholar
- Boylan JF, Gudas LJ: The level of CRABP-I expression influences the amounts and types of all-trans-retinoic acid metabolites in F9 teratocarcinoma stem cells. J Biol Chem. 1992, 267 (30): 21486-21491.PubMedGoogle Scholar
- Gu X, Xu F, Wang X, Gao X, Zhao Q: Molecular cloning and expression of a novel CYP26 gene (cyp26d1) during zebrafish early development. Gene Expr Patterns. 2005, 5 (6): 733-739. 10.1016/j.modgep.2005.04.005PubMedView ArticleGoogle Scholar
- Sakai Y, Luo T, McCaffery P, Hamada H, Drager UC: CYP26A1 and CYP26C1 cooperate in degrading retinoic acid within the equatorial retina during later eye development. Dev Biol. 2004, 276 (1): 143-157. 10.1016/j.ydbio.2004.08.032PubMedView ArticleGoogle Scholar
- Takeuchi H, Yokota A, Ohoka Y, Iwata M: Cyp26b1 regulates retinoic acid-dependent signals in T cells and its expression is inhibited by transforming growth factor-beta. PLoS One. 6 (1): e16089.Google Scholar
- Hernandez RE, Putzke AP, Myers JP, Margaretha L, Moens CB: Cyp26 enzymes generate the retinoic acid response pattern necessary for hindbrain development. Development. 2007, 134 (1): 177-187. 10.1242/dev.02706PubMed CentralPubMedView ArticleGoogle Scholar
- White JA, Beckett-Jones B, Guo YD, Dilworth FJ, Bonasoro J, Jones G, Petkovich M: cDNA cloning of human retinoic acid-metabolizing enzyme (hP450RAI) identifies a novel family of cytochromes P450. J Biol Chem. 1997, 272 (30): 18538-18541. 10.1074/jbc.272.30.18538PubMedView ArticleGoogle Scholar
- de Roos K, Sonneveld E, Compaan B, ten Berge D, Durston AJ, van der Saag PT: Expression of retinoic acid 4-hydroxylase (CYP26) during mouse and Xenopus laevis embryogenesis. Mech Dev. 1999, 82 (1-2): 205-211. 10.1016/S0925-4773(99)00016-7PubMedView ArticleGoogle Scholar
- Swindell EC, Thaller C, Sockanathan S, Petkovich M, Jessell TM, Eichele G: Complementary domains of retinoic acid production and degradation in the early chick embryo. Dev Biol. 1999, 216 (1): 282-296. 10.1006/dbio.1999.9487PubMedView ArticleGoogle Scholar
- Giguere V, Ong ES, Segui P, Evans RM: Identification of a receptor for the morphogen retinoic acid. Nature. 1987, 330 (6149): 624-629. 10.1038/330624a0PubMedView ArticleGoogle Scholar
- Petkovich M, Brand NJ, Krust A, Chambon P: A human retinoic acid receptor which belongs to the family of nuclear receptors. Nature. 1987, 330 (6147): 444-450. 10.1038/330444a0PubMedView ArticleGoogle Scholar
- Brand N, Petkovich M, Krust A, Chambon P, de The H, Marchio A, Tiollais P, Dejean A: Identification of a second human retinoic acid receptor. Nature. 1988, 332 (6167): 850-853. 10.1038/332850a0PubMedView ArticleGoogle Scholar
- 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 (2): 213-222.PubMedGoogle Scholar
- Li E, Sucov HM, Lee KF, Evans RM, Jaenisch R: Normal development and growth of mice carrying a targeted disruption of the alpha 1 retinoic acid receptor gene. Proc Natl Acad Sci USA. 1993, 90 (4): 1590-1594. 10.1073/pnas.90.4.1590PubMed CentralPubMedView ArticleGoogle Scholar
- Ghyselinck NB, Dupe V, Dierich A, Messaddeq N, Garnier JM, Rochette-Egly C, Chambon P, Mark M: Role of the retinoic acid receptor beta (RARbeta) during mouse development. Int J Dev Biol. 1997, 41 (3): 425-447.PubMedGoogle Scholar
- Subbarayan V, Kastner P, Mark M, Dierich A, Gorry P, Chambon P: Limited specificity and large overlap of the functions of the mouse RAR gamma 1 and RAR gamma 2 isoforms. Mech Dev. 1997, 66 (1-2): 131-142. 10.1016/S0925-4773(97)00098-1PubMedView ArticleGoogle Scholar
- Manshouri T, Yang Y, Lin H, Stass SA, Glassman AB, Keating MJ, Albitar M: Downregulation of RAR alpha in mice by antisense transgene leads to a compensatory increase in RAR beta and RAR gamma and development of lymphoma. Blood. 1997, 89 (7): 2507-2515.PubMedGoogle Scholar
- Mark M, Ghyselinck NB, Wendling O, Dupe V, Mascrez B, Kastner P, Chambon P: A genetic dissection of the retinoid signalling pathway in the mouse. Proc Nutr Soc. 1999, 58 (3): 609-613. 10.1017/S0029665199000798PubMedView ArticleGoogle Scholar
- Chomienne C, Balitrand N, Ballerini P, Castaigne S, de The H, Degos L: All-trans retinoic acid modulates the retinoic acid receptor-alpha in promyelocytic cells. J Clin Invest. 1991, 88 (6): 2150-2154. 10.1172/JCI115547PubMed CentralPubMedView ArticleGoogle Scholar
- Kamei Y, Kawada T, Kazuki R, Sugimoto E: Retinoic acid receptor gamma 2 gene expression is up-regulated by retinoic acid in 3T3-L1 preadipocytes. Biochem J. 1993, 293 (Pt 3): 807-812.PubMed CentralPubMedView ArticleGoogle Scholar
- Sucov HM, Murakami KK, Evans RM: Characterization of an autoregulated response element in the mouse retinoic acid receptor type beta gene. Proc Natl Acad Sci USA. 1990, 87 (14): 5392-5396. 10.1073/pnas.87.14.5392PubMed CentralPubMedView ArticleGoogle Scholar
- Chawla A, Repa JJ, Evans RM, Mangelsdorf DJ: Nuclear receptors and lipid physiology: opening the X-files. Science. 2001, 294 (5548): 1866-1870. 10.1126/science.294.5548.1866PubMedView ArticleGoogle Scholar
- Kastner P, Messaddeq N, Mark M, Wendling O, Grondona JM, Ward S, Ghyselinck N, Chambon P: Vitamin A deficiency and mutations of RXRalpha, RXRbeta and RARalpha lead to early differentiation of embryonic ventricular cardiomyocytes. Development. 1997, 124 (23): 4749-4758.PubMedGoogle Scholar
- Kastner P, Mark M, Leid M, Gansmuller A, Chin W, Grondona JM, Decimo D, Krezel W, Dierich A, Chambon P: Abnormal spermatogenesis in RXR beta mutant mice. Genes Dev. 1996, 10 (1): 80-92. 10.1101/gad.10.1.80PubMedView ArticleGoogle Scholar
- Krezel W, Dupe V, Mark M, Dierich A, Kastner P, Chambon P: RXR gamma null mice are apparently normal and compound RXR alpha +/-/RXR beta -/-/RXR gamma -/- mutant mice are viable. Proc Natl Acad Sci USA. 1996, 93 (17): 9010-9014.PubMed CentralPubMedView ArticleGoogle Scholar
- Mello T, Polvani S, Galli A: Peroxisome proliferator-activated receptor and retinoic x receptor in alcoholic liver disease. PPAR Res. 2009, 2009: 748174.PubMed CentralPubMedView ArticleGoogle Scholar
- Rizzo G, Renga B, Antonelli E, Passeri D, Pellicciari R, Fiorucci S: The methyl transferase PRMT1 functions as co-activator of farnesoid X receptor (FXR)/9-cis retinoid X receptor and regulates transcription of FXR responsive genes. Mol Pharmacol. 2005, 68 (2): 551-558. 10.1124/mol.105.012104PubMedView ArticleGoogle Scholar
- Wingert RA, Davidson AJ: The zebrafish pronephros: a model to study nephron segmentation. Kidney Int. 2008, 73 (10): 1120-1127. 10.1038/ki.2008.37PubMedView ArticleGoogle Scholar
- Lagu B, Pio B, Lebedev R, Yang M, Pelton PD: RXR-LXR heterodimer modulators for the potential treatment of dyslipidemia. Bioorg Med Chem Lett. 2007, 17 (12): 3497-3503. 10.1016/j.bmcl.2007.01.047PubMedView ArticleGoogle Scholar
- Zhao C, Dahlman-Wright K: Liver X receptor in cholesterol metabolism. J Endocrinol. 204 (3): 233-240.Google Scholar
- Desvergne B: RXR: from partnership to leadership in metabolic regulations. Vitam Horm. 2007, 75: 1-32.PubMedView ArticleGoogle Scholar
- Desvergne B, Wahli W: Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev. 1999, 20 (5): 649-688. 10.1210/er.20.5.649PubMedGoogle Scholar
- Desvergne B, Michalik L, Wahli W: Transcriptional regulation of metabolism. Physiol Rev. 2006, 86 (2): 465-514. 10.1152/physrev.00025.2005PubMedView ArticleGoogle Scholar
- Hollemann T, Chen Y, Grunz H, Pieler T: Regionalized metabolic activity establishes boundaries of retinoic acid signalling. EMBO J. 1998, 17 (24): 7361-7372. 10.1093/emboj/17.24.7361PubMed CentralPubMedView ArticleGoogle Scholar
- Astrom A, Pettersson U, Voorhees JJ: Structure of the human cellular retinoic acid-binding protein II gene. Early transcriptional regulation by retinoic acid. J Biol Chem. 1992, 267 (35): 25251-25255.PubMedGoogle Scholar
- 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 (1): 73-85. 10.1016/0092-8674(92)90267-GPubMedView ArticleGoogle Scholar
- Zhu J, Heyworth CM, Glasow A, Huang QH, Petrie K, Lanotte M, Benoit G, Gallagher R, Waxman S, Enver T: Lineage restriction of the RARalpha gene expression in myeloid differentiation. Blood. 2001, 98 (8): 2563-2567. 10.1182/blood.V98.8.2563PubMedView ArticleGoogle Scholar
- Takeyama K, Kojima R, Ohashi R, Sato T, Mano H, Masushige S, Kato S: Retinoic acid differentially up-regulates the gene expression of retinoic acid receptor alpha and gamma isoforms in embryo and adult rats. Biochem Biophys Res Commun. 1996, 222 (2): 395-400. 10.1006/bbrc.1996.0755PubMedView ArticleGoogle Scholar
- Halme A, Cheng M, Hariharan IK: Retinoids regulate a developmental checkpoint for tissue regeneration in Drosophila. Curr Biol. 20 (5): 458-463.Google Scholar
- Maden M: Retinoids in nonmammalian embryos. Methods Mol Biol. 2008, 461: 541-559. 10.1007/978-1-60327-483-8_37PubMedView ArticleGoogle Scholar
- Uehara M, Yashiro K, Takaoka K, Yamamoto M, Hamada H: Removal of maternal retinoic acid by embryonic CYP26 is required for correct Nodal expression during early embryonic patterning. Genes Dev. 2009, 23 (14): 1689-1698. 10.1101/gad.1776209PubMed CentralPubMedView ArticleGoogle Scholar
- Kudoh T, Wilson SW, Dawid IB: Distinct roles for Fgf, Wnt and retinoic acid in posteriorizing the neural ectoderm. Development. 2002, 129 (18): 4335-4346.PubMedGoogle Scholar
- White RJ, Schilling TF: How degrading: Cyp26s in hindbrain development. Dev Dyn. 2008, 237 (10): 2775-2790. 10.1002/dvdy.21695PubMed CentralPubMedView ArticleGoogle Scholar
- Kessel M, Gruss P: Homeotic transformations of murine vertebrae and concomitant alteration of Hox codes induced by retinoic acid. Cell. 1991, 67 (1): 89-104. 10.1016/0092-8674(91)90574-IPubMedView ArticleGoogle Scholar
- Padmanabhan R: Retinoic acid-induced caudal regression syndrome in the mouse fetus. Reprod Toxicol. 1998, 12 (2): 139-151. 10.1016/S0890-6238(97)00153-6PubMedView ArticleGoogle Scholar
- Durston AJ, Timmermans JP, Hage WJ, Hendriks HF, de Vries NJ, Heideveld M, Nieuwkoop PD: Retinoic acid causes an anteroposterior transformation in the developing central nervous system. Nature. 1989, 340 (6229): 140-144. 10.1038/340140a0PubMedView ArticleGoogle Scholar
- Sive HL, Draper BW, Harland RM, Weintraub H: Identification of a retinoic acid-sensitive period during primary axis formation in Xenopus laevis. Genes Dev. 1990, 4 (6): 932-942. 10.1101/gad.4.6.932PubMedView ArticleGoogle Scholar
- Ruiz i Altaba A, Jessell TM: Retinoic acid modifies the pattern of cell differentiation in the central nervous system of neurula stage Xenopus embryos. Development. 1991, 112 (4): 945-958.PubMedGoogle Scholar
- Chazaud C, Chambon P, Dolle P: Retinoic acid is required in the mouse embryo for left-right asymmetry determination and heart morphogenesis. Development. 1999, 126 (12): 2589-2596.PubMedGoogle Scholar
- Huang S, Ma J, Liu X, Zhang Y, Luo L: Retinoic acid signaling sequentially controls visceral and heart laterality in zebrafish. J Biol Chem. 286 (32): 28533-28543.Google Scholar
- 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 (5721): 563-566. 10.1126/science.1108363PubMedView ArticleGoogle Scholar
- Vermot J, Pourquie O: Retinoic acid coordinates somitogenesis and left-right patterning in vertebrate embryos. Nature. 2005, 435 (7039): 215-220. 10.1038/nature03488PubMedView ArticleGoogle Scholar
- Anderson DJ: Lineages and transcription factors in the specification of vertebrate primary sensory neurons. Curr Opin Neurobiol. 1999, 9 (5): 517-524. 10.1016/S0959-4388(99)00015-XPubMedView ArticleGoogle Scholar
- Ribes V, Stutzmann F, Bianchetti L, Guillemot F, Dolle P, Le Roux I: Combinatorial signalling controls Neurogenin2 expression at the onset of spinal neurogenesis. Dev Biol. 2008, 321 (2): 470-481. 10.1016/j.ydbio.2008.06.003PubMedView ArticleGoogle Scholar
- Coyle DE, Li J, Baccei M: Regional differentiation of retinoic acid-induced human pluripotent embryonic carcinoma stem cell neurons. PLoS One. 2011, 6 (1): e16174. 10.1371/journal.pone.0016174PubMed CentralPubMedView ArticleGoogle Scholar
- Shan ZY, Liu F, Lei L, Li QM, Jin LH, Wu YS, Li X, Shen JL: Generation of dorsal spinal cord GABAergic neurons from mouse embryonic stem cells. Cell Reprogram. 2011, 13 (1): 85-91.PubMedView ArticleGoogle Scholar
- Chen N, Napoli JL: All-trans-retinoic acid stimulates translation and induces spine formation in hippocampal neurons through a membrane-associated RARalpha. FASEB J. 2008, 22 (1): 236-245.PubMedView ArticleGoogle Scholar
- Krumlauf R: Hox genes and pattern formation in the branchial region of the vertebrate head. Trends Genet. 1993, 9 (4): 106-112. 10.1016/0168-9525(93)90203-TPubMedView ArticleGoogle Scholar
- Studer M, Lumsden A, Ariza-McNaughton L, Bradley A, Krumlauf R: Altered segmental identity and abnormal migration of motor neurons in mice lacking Hoxb-1. Nature. 1996, 384 (6610): 630-634. 10.1038/384630a0PubMedView ArticleGoogle Scholar
- Marshall H, Nonchev S, Sham MH, Muchamore I, Lumsden A, Krumlauf R: Retinoic acid alters hindbrain Hox code and induces transformation of rhombomeres 2/3 into a 4/5 identity. Nature. 1992, 360 (6406): 737-741. 10.1038/360737a0PubMedView ArticleGoogle Scholar
- Kessel M: Reversal of axonal pathways from rhombomere 3 correlates with extra Hox expression domains. Neuron. 1993, 10 (3): 379-393. 10.1016/0896-6273(93)90328-OPubMedView ArticleGoogle Scholar
- Hill J, Clarke JD, Vargesson N, Jowett T, Holder N: Exogenous retinoic acid causes specific alterations in the development of the midbrain and hindbrain of the zebrafish embryo including positional respecification of the Mauthner neuron. Mech Dev. 1995, 50 (1): 3-16. 10.1016/0925-4773(94)00321-DPubMedView ArticleGoogle Scholar
- Hernandez RE, Rikhof HA, Bachmann R, Moens CB: vhnf1 integrates global RA patterning and local FGF signals to direct posterior hindbrain development in zebrafish. Development. 2004, 131 (18): 4511-4520. 10.1242/dev.01297PubMedView ArticleGoogle Scholar
- Wiellette EL, Sive H: vhnf1 and Fgf signals synergize to specify rhombomere identity in the zebrafish hindbrain. Development. 2003, 130 (16): 3821-3829. 10.1242/dev.00572PubMedView ArticleGoogle Scholar
- Begemann G, Meyer A: Hindbrain patterning revisited: timing and effects of retinoic acid signalling. Bioessays. 2001, 23 (11): 981-986. 10.1002/bies.1142PubMedView ArticleGoogle Scholar
- Gavalas A: ArRAnging the hindbrain. Trends Neurosci. 2002, 25 (2): 61-64. 10.1016/S0166-2236(02)02067-2PubMedView ArticleGoogle Scholar
- Dupe V, Lumsden A: Hindbrain patterning involves graded responses to retinoic acid signalling. Development. 2001, 128 (12): 2199-2208.PubMedGoogle Scholar
- Begemann G, Schilling TF, Rauch GJ, Geisler R, Ingham PW: The zebrafish neckless mutation reveals a requirement for raldh2 in mesodermal signals that pattern the hindbrain. Development. 2001, 128 (16): 3081-3094.PubMedGoogle Scholar
- Partanen J: FGF signalling pathways in development of the midbrain and anterior hindbrain. J Neurochem. 2007, 101 (5): 1185-1193. 10.1111/j.1471-4159.2007.04463.xPubMedView ArticleGoogle Scholar
- 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 (2): 415-427. 10.1016/j.ydbio.2004.11.023PubMedView ArticleGoogle Scholar
- Chen Y, Pan FC, Brandes N, Afelik S, Solter M, Pieler T: Retinoic acid signaling is essential for pancreas development and promotes endocrine at the expense of exocrine cell differentiation in Xenopus. Dev Biol. 2004, 271 (1): 144-160. 10.1016/j.ydbio.2004.03.030PubMedView ArticleGoogle Scholar
- Stafford D, Hornbruch A, Mueller PR, Prince VE: A conserved role for retinoid signaling in vertebrate pancreas development. Dev Genes Evol. 2004, 214 (9): 432-441.PubMedView ArticleGoogle Scholar
- 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 (2): 399-411. 10.1016/j.ydbio.2005.05.035PubMedView ArticleGoogle Scholar
- Molotkov A, Molotkova N, Duester G: Retinoic acid generated by Raldh2 in mesoderm is required for mouse dorsal endodermal pancreas development. Dev Dyn. 2005, 232 (4): 950-957. 10.1002/dvdy.20256PubMedView ArticleGoogle Scholar
- Pan FC, Chen Y, Bayha E, Pieler T: Retinoic acid-mediated patterning of the pre-pancreatic endoderm in Xenopus operates via direct and indirect mechanisms. Mech Dev. 2007, 124 (7-8): 518-531. 10.1016/j.mod.2007.06.003PubMedView ArticleGoogle Scholar
- Bayha E, Jorgensen MC, Serup P, Grapin-Botton A: Retinoic acid signaling organizes endodermal organ specification along the entire antero-posterior axis. PLoS One. 2009, 4 (6): e5845. 10.1371/journal.pone.0005845PubMed CentralPubMedView ArticleGoogle Scholar
- Stafford D, Prince VE: Retinoic acid signaling is required for a critical early step in zebrafish pancreatic development. Curr Biol. 2002, 12 (14): 1215-1220. 10.1016/S0960-9822(02)00929-6PubMedView ArticleGoogle Scholar
- Stafford D, White RJ, Kinkel MD, Linville A, Schilling TF, Prince VE: Retinoids signal directly to zebrafish endoderm to specify insulin-expressing beta-cells. Development. 2006, 133 (5): 949-956. 10.1242/dev.02263PubMedView ArticleGoogle Scholar
- Dalgin G, Ward AB, Hao le T, Beattie CE, Nechiporuk A, Prince VE: Zebrafish mnx1 controls cell fate choice in the developing endocrine pancreas. Development. 138 (21): 4597-4608.Google Scholar
- Kinkel MD, Prince VE: On the diabetic menu: zebrafish as a model for pancreas development and function. Bioessays. 2009, 31 (2): 139-152. 10.1002/bies.200800123PubMed CentralPubMedView ArticleGoogle Scholar
- Kinkel MD, Eames SC, Alonzo MR, Prince VE: Cdx4 is required in the endoderm to localize the pancreas and limit beta-cell number. Development. 2008, 135 (5): 919-929. 10.1242/dev.010660PubMedView ArticleGoogle Scholar
- Ostrom M, Loffler KA, Edfalk S, Selander L, Dahl U, Ricordi C, Jeon J, Correa-Medina M, Diez J, Edlund H: Retinoic acid promotes the generation of pancreatic endocrine progenitor cells and their further differentiation into beta-cells. PLoS One. 2008, 3 (7): e2841. 10.1371/journal.pone.0002841PubMed CentralPubMedView ArticleGoogle Scholar
- Tulachan SS, Doi R, Kawaguchi Y, Tsuji S, Nakajima S, Masui T, Koizumi M, Toyoda E, Mori T, Ito D: All-trans retinoic acid induces differentiation of ducts and endocrine cells by mesenchymal/epithelial interactions in embryonic pancreas. Diabetes. 2003, 52 (1): 76-84. 10.2337/diabetes.52.1.76PubMedView ArticleGoogle Scholar
- Shen CN, Marguerie A, Chien CY, Dickson C, Slack JM, Tosh D: All-trans retinoic acid suppresses exocrine differentiation and branching morphogenesis in the embryonic pancreas. Differentiation. 2007, 75 (1): 62-74.PubMed CentralPubMedView ArticleGoogle Scholar
- Moriya N, Komazaki S, Takahashi S, Yokota C, Asashima M: In vitro pancreas formation from Xenopus ectoderm treated with activin and retinoic acid. Dev Growth Differ. 2000, 42 (6): 593-602. 10.1046/j.1440-169x.2000.00542.xPubMedView ArticleGoogle Scholar
- Asashima M, Michiue T, Kurisaki A: Elucidation of the role of activin in organogenesis using a multiple organ induction system with amphibian and mouse undifferentiated cells in vitro. Dev Growth Differ. 2008, 50 (Suppl 1): S35-45.PubMedView ArticleGoogle Scholar
- Heine UI, Roberts AB, Munoz EF, Roche NS, Sporn MB: Effects of retinoid deficiency on the development of the heart and vascular system of the quail embryo. Virchows Arch B Cell Pathol Incl Mol Pathol. 1985, 50 (2): 135-152.PubMedGoogle Scholar
- Lin SC, Dolle P, Ryckebusch L, Noseda M, Zaffran S, Schneider MD, Niederreither K: Endogenous retinoic acid regulates cardiac progenitor differentiation. Proc Natl Acad Sci USA. 2010, 107 (20): 9234-9239. 10.1073/pnas.0910430107PubMed CentralPubMedView ArticleGoogle Scholar
- Sirbu IO, Zhao X, Duester G: Retinoic acid controls heart anteroposterior patterning by down-regulating Isl1 through the Fgf8 pathway. Dev Dyn. 2008, 237 (6): 1627-1635. 10.1002/dvdy.21570PubMed CentralPubMedView ArticleGoogle Scholar
- Stachurska E, Loboda A, Niderla-Bielinska J, Szperl M, Juszynski M, Jozkowicz A, Dulak J, Ratajska A: Expression of cellular retinoic acid-binding protein I and II (CRABP I and II) in embryonic mouse hearts treated with retinoic acid. Acta Biochim Pol. 2011, 58 (1): 19-29.PubMedGoogle Scholar
- Keegan BR, Feldman JL, Begemann G, Ingham PW, Yelon D: Retinoic acid signaling restricts the cardiac progenitor pool. Science. 2005, 307 (5707): 247-249. 10.1126/science.1101573PubMedView ArticleGoogle Scholar
- Ryckebusch L, Wang Z, Bertrand N, Lin SC, Chi X, Schwartz R, Zaffran S, Niederreither K: Retinoic acid deficiency alters second heart field formation. Proc Natl Acad Sci USA. 2008, 105 (8): 2913-2918. 10.1073/pnas.0712344105PubMed CentralPubMedView ArticleGoogle Scholar
- Mathew LK, Sengupta S, Franzosa JA, Perry J, La Du J, Andreasen EA, Tanguay RL: Comparative expression profiling reveals an essential role for raldh2 in epimorphic regeneration. J Biol Chem. 2009, 284 (48): 33642-33653. 10.1074/jbc.M109.011668PubMed CentralPubMedView ArticleGoogle Scholar
- Kikuchi K, Holdway JE, Major RJ, Blum N, Dahn RD, Begemann G, Poss KD: Retinoic acid production by endocardium and epicardium is an injury response essential for zebrafish heart regeneration. Dev Cell. 20 (3): 397-404.Google Scholar
- Serluca FC, Fishman MC: Pre-pattern in the pronephric kidney field of zebrafish. Development. 2001, 128 (12): 2233-2241.PubMedGoogle Scholar
- Cartry J, Nichane M, Ribes V, Colas A, Riou JF, Pieler T, Dolle P, Bellefroid EJ, Umbhauer M: Retinoic acid signalling is required for specification of pronephric cell fate. Dev Biol. 2006, 299 (1): 35-51. 10.1016/j.ydbio.2006.06.047PubMedView ArticleGoogle Scholar
- 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 (10): 2749-2771.PubMedGoogle Scholar
- Carroll TJ, Vize PD: Synergism between Pax-8 and lim-1 in embryonic kidney development. Dev Biol. 1999, 214 (1): 46-59. 10.1006/dbio.1999.9414PubMedView ArticleGoogle Scholar
- Lee SJ, Kim S, Choi SC, Han JK: XPteg (Xenopus proximal tubules-expressed gene) is essential for pronephric mesoderm specification and tubulogenesis. Mech Dev. 2010, 127 (1-2): 49-61. 10.1016/j.mod.2009.11.001PubMedView ArticleGoogle Scholar
- Bollig F, Perner B, Besenbeck B, Kothe S, Ebert C, Taudien S, Englert C: A highly conserved retinoic acid responsive element controls wt1a expression in the zebrafish pronephros. Development. 2009, 136 (17): 2883-2892. 10.1242/dev.031773PubMedView ArticleGoogle Scholar
- Perner B, Englert C, Bollig F: The Wilms tumor genes wt1a and wt1b control different steps during formation of the zebrafish pronephros. Dev Biol. 2007, 309 (1): 87-96. 10.1016/j.ydbio.2007.06.022PubMedView ArticleGoogle Scholar
- Osafune K, Nishinakamura R, Komazaki S, Asashima M: In vitro induction of the pronephric duct in Xenopus explants. Dev Growth Differ. 2002, 44 (2): 161-167. 10.1046/j.1440-169x.2002.00631.xPubMedView ArticleGoogle Scholar
- Wingert RA, Selleck R, Yu J, Song HD, Chen Z, Song A, Zhou Y, Thisse B, Thisse C, McMahon AP: The cdx genes and retinoic acid control the positioning and segmentation of the zebrafish pronephros. PLoS Genet. 2007, 3 (10): 1922-1938.PubMedView ArticleGoogle Scholar
- Rosselot C, Spraggon L, Chia I, Batourina E, Riccio P, Lu B, Niederreither K, Dolle P, Duester G, Chambon P: Non-cell-autonomous retinoid signaling is crucial for renal development. Development. 137 (2): 283-292.Google Scholar
- Desai TJ, Malpel S, Flentke GR, Smith SM, Cardoso WV: Retinoic acid selectively regulates Fgf10 expression and maintains cell identity in the prospective lung field of the developing foregut. Dev Biol. 2004, 273 (2): 402-415. 10.1016/j.ydbio.2004.04.039PubMedView ArticleGoogle Scholar
- Desai TJ, Chen F, Lu J, Qian J, Niederreither K, Dolle P, Chambon P, Cardoso WV: Distinct roles for retinoic acid receptors alpha and beta in early lung morphogenesis. Dev Biol. 2006, 291 (1): 12-24. 10.1016/j.ydbio.2005.10.045PubMedView ArticleGoogle Scholar
- Chen F, Cao Y, Qian J, Shao F, Niederreither K, Cardoso WV: A retinoic acid-dependent network in the foregut controls formation of the mouse lung primordium. J Clin Invest. 120 (6): 2040-2048.Google Scholar
- Malpel S, Mendelsohn C, Cardoso WV: Regulation of retinoic acid signaling during lung morphogenesis. Development. 2000, 127 (14): 3057-3067.PubMedGoogle Scholar
- Shiotsugu J, Katsuyama Y, Arima K, Baxter A, Koide T, Song J, Chandraratna RA, Blumberg B: Multiple points of interaction between retinoic acid and FGF signaling during embryonic axis formation. Development. 2004, 131 (11): 2653-2667. 10.1242/dev.01129PubMedView ArticleGoogle Scholar
- Ho L, Mercola M, Gudas LJ: Xenopus laevis cellular retinoic acid-binding protein: temporal and spatial expression pattern during early embryogenesis. Mech Dev. 1994, 47 (1): 53-64. 10.1016/0925-4773(94)90095-7PubMedView ArticleGoogle Scholar
- Kam RK, Chen Y, Chan SO, Chan WY, Dawid IB, Zhao H: Developmental expression of Xenopus short-chain dehydrogenase/reductase 3. Int J Dev Biol. 2010, 54 (8-9): 1355-1360. 10.1387/ijdb.092984rkPubMed CentralPubMedView ArticleGoogle Scholar
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