Vitamin A in Reproduction and Development

“There are three major subtypes of RAR protein (α, β and γ) with additional isoforms resulting from alternate promoter usage and splicing [29].”

“RAREs serve as enhancer elements and when occupied by the RA/RAR/RXR complex, facilitate chromatin opening and changes in RA target gene transcriptional activity [34,35].”

“pancreatic buds to grow and differentiate [279–281].”

“Using dietary manipulation to induce deficiency in rats, the importance of vitamin A in both male and female reproduction was soon discovered [2,3].”

“Much of the craniofacial skeleton originates from neural crest cells [226].”

“RALDH2 null mutant mice lack nephric ducts [123] and in RARα/β2 double receptor mutants, nephron progenitors, stromal cells and ureteric bud tips are all greatly reduced or completely absent at birth [98,236].”

“5 in the mouse [136].”

“5 rat), produces anterior transformations starting at vertebrae 15 (thoracic vertebra 8, T8) whereas excess RA at even later times, yields both rostral posteriorizing and caudal anteriorizations [223,224].”

“Raldh2 is largely responsible for RA synthesis in the mesonephros, with some contribution from Raldh3 in the region of the mesonephric duct [71,80].”

“genes are altered when cells or tissues are exposed to RA, however, only a small subset are primary (direct) targets via RARE-mediated transcription, with the remainder representing downstream targets [36,37].”

“Vitamin A is required for many aspects of nervous system development including patterning and neural differentiation [157,158].”

“for a membrane RBP receptor [26,250], as well as to CDH-affected chromosome loci encoding for several other retinoid-related genes [251].”

“RAREs serve as enhancer elements and when occupied by the RA/RAR/RXR complex, facilitate chromatin opening and changes in RA target gene transcriptional activity [34,35].”

“Summary of abnormalities in VAD rat embryos given insufficient RA (late VAD) * [67], insufficient carotene (VAD syndrome) [95], or observed in RAR null mutants [97–99].”

“Expression of a β2-RARE-lacZ (RARE-lacZ) transgene that is activated in reporter mice when retinoid interacts with the RAR, has been used extensively as a marker of retinoid-signaling activity in vivo [147].”

“A reduction in FGF in the presomitic mesoderm below a threshold value is needed to position the future somite boundary [218,219].”

“Genetic deletion of several RARs produces defects in axial development with anterior cervical transformations similar to VAD embryos [53,97,209].”

“importance of the RAR in mediating the actions of RA in developing embryos [99,101,102].”

“RARα null mutants are sterile and show a reduction in spermatozoa, indicating that nuclear RAR is needed for spermiation [54].”

“This is followed by the later expression of Cyp26A1 in r2 and Cyp26C1 in r2 and r4 [18,21,139,144].”

“Vitamin A and metabolites are lipophilic compounds that are generally found in association with serum and cellular binding proteins [24].”

“Raldh2 is first expressed during gastrulation in the mesenchyme adjacent to the node and the primitive streak [148].”

“However, too much RA at critical stages can result in embryo lethality or malformation [117–120].”

“female gonocytes [76].”

“Additional information regarding the role of RA in pancreas development can be found in several recent reviews [283,284].”

“RA has been proposed to play a role in patterning the developing limb by regulating the pattern of expression of genes such as Hand2 (activates SHH), Shh (patterns the anterior-to-posterior axis), and Meis1/2 (transcription factors that mark the proximal limb bud mesenchyme) [287,290–292].”

“In the female, the effect of vitamin A deficiency on reproductive outcome is dependent upon the time when deficiency is imposed, as well as its severity [58].”

“Hox gene expression appears to be major way in which retinoids affect positional information along the anteroposterior body axis [222–225].”

“character [139,140], however, individual CYP26B1 and CYP26C1 mutants develop normally [143,144].”

“family (A1, B1 and C1) [17–23].”

“division, resulting in the formation of neurons or intermediate progenitor cells [185].”

“Cyp1B1 can also generate RA and is expressed at known sites of RALDH-independent retinoid signaling [16], however, null mutant mice for this gene are viable [137].”

“motor neurons [190,191].”

“(A) Metabolic scheme proposed by Dowling and Wald in 1960 [11]; (B) Mechanism ca.”

“If provided in adequate amounts, retinol will support reproduction and embryonic development in full [62].”

“This is followed by the later expression of Cyp26A1 in r2 and Cyp26C1 in r2 and r4 [18,21,139,144].”

“Recent work supports the conclusion that the vitamin A metabolite, RA, is needed both for adult male spermatogonial differentiation (transition to A1) and the entrance into meiosis [45–47].”

“testis by postnatal day 6 [84] and spermatogenesis begins shortly thereafter [85].”

“importance of the RAR in mediating the actions of RA in developing embryos [99,101,102].”

“for a membrane RBP receptor [26,250], as well as to CDH-affected chromosome loci encoding for several other retinoid-related genes [251].”

“male embryo, this pathway is blocked by the action of CYP26B1, but is enabled after birth [70–73].”

“RA is also linked to the promotion of neurite outgrowth [157,162].”

“motor neurons [190,191].”

“Congenital diaphragmatic hernia (CDH) occurs in approximately one in 3000 births, and is associated with high neonatal mortality [248].”

“mice; some have been found to be dispensable, while roles for others have been revealed when animals are fed a vitamin A-restricted diet [12,27,28].”

“In 1913 McCollum and Davis reported that the addition of an ether extract from egg yolk or butter, but not lard or olive oil, could reinstate growth in rats maintained for several months on a purified ration of casein, carbohydrates and salt mixtures [1].”

“Mice null for RALDH2 or RDH10, also have lung agenesis or hypoplastic phenotypes [122,258,259].”

“RA has been proposed to play a role in patterning the developing limb by regulating the pattern of expression of genes such as Hand2 (activates SHH), Shh (patterns the anterior-to-posterior axis), and Meis1/2 (transcription factors that mark the proximal limb bud mesenchyme) [287,290–292].”

“In kidney, the number of embryonic branching events determines the final number of nephrons an individual will have for life, and it has been proposed that suboptimal nephron number at birth increases susceptibility to acquired renal disease and essential hypertension later in life [243–246].”

“RA acting through the RAR is also necessary for the morphogenesis of other components of the respiratory tract including partitioning of the primitive foregut into oesophagus and trachea, and for the opening between the nasal and oropharyngeal cavities [67,131,209,256,258,261].”

“These studies show that controlled exclusion of RA from the limb bud is essential for proper limb morphology [142].”

“The effects of RA deficiency on pancreatic lineages appear to be due to the loss of pancreatic field specification within the endoderm [274].”

“reports that exogenous RA can stimulate alveoli formation in immature rat and mouse lung [264–269].”

“null mutant mice, a requirement for RA in pancreatic development has been proposed based on studies in RALDH null mutant mice [271,272] and in several other organisms in which retinoid signaling is deficient or inhibited, including Xenopus, zebrafish, chick, and quail [273–276].”

“5, and this is followed by apoptosis [73].”

“comprises the caudal end of the node and the rostral end of the primitive streak [186].”

“However, too much RA at critical stages can result in embryo lethality or malformation [117–120].”

“mutants rescues renal development, restoring ureteric bud growth and stromal cell patterning [237].”

“RA plays a role in the initiation of differentiation of the anterior region of the presomitic mesoderm from which the new somites originate [217].”

“reviews [229,232,234].”

“Recent work supports the conclusion that the vitamin A metabolite, RA, is needed both for adult male spermatogonial differentiation (transition to A1) and the entrance into meiosis [45–47].”

“The nuclear RARs act as ligand-activated transcription factors to regulate gene transcription in a cell-type and tissue-specific manner [30].”

“Cardiac and aortic arch defects were observed as a part of the early vitamin A deficiency syndrome in rat embryos [93,94] and in RAR compound null mutant mouse embryos [98,102].”

“testis by postnatal day 6 [84] and spermatogenesis begins shortly thereafter [85].”

“Within the normal tubule, the Sertoli cell is believed to generate RA by the action of Raldh1 [49,51,52], and possibly Raldh2 [50].”

“A number of eye defects in RALDH3 and RALDH1/3 compound mutants [134,135,178] are also similar to those observed in late VAD rat embryos.”

“family (A1, B1 and C1) [17–23].”

“(Adapted from [77,78]).”

“In the embryonic kidney, Raldh2 is localized in stromal mesenchyme of the outer cortex and Raldh3 is expressed in the ureteric bud [130,237,238].”

“Interestingly, in Cyp26 morpholino studies in zebrafish, restriction of the RA-responsive gene, Vhnff1, is determined by the posterior limit of Cyp26C1 at the r4/r5 boundary, a function that can be compensated for by CYP26B1 [173].”

“However, work from the Duester group indicates that ligand binding to the RAR is sufficient to transduce the signal, as a RAR- but not a RXR- selective ligand is able to rescue the developmental defects in RALDH2 null mutant embryos [108].”

“number of RAR mutants show both cervical anteriorizations and posteriorization at the cervical thoracic junction [97,209].”

“This problem was solved when Moore fed carotenoids to vitamin A-deficient (VAD) rats in amounts that enabled the animals to resume normal growth, and showed that only the ―colorless‖ form of vitamin A was found in the livers collected from these animals [5].”

“However, too much RA at critical stages can result in embryo lethality or malformation [117–120].”

“RAR/RXR heterodimers form the functional unit that transduces the RA signal, with one genomic copy of the Rxrα sufficient to support RXR function in embryogenesis [105].”

“Deletion of RALDH2 is lethal early in development, whereas RALDH3 null mutants die at birth [131], and RALDH1 mutants are viable [133].”

“However, too much RA at critical stages can result in embryo lethality or malformation [117–120].”

“reports that exogenous RA can stimulate alveoli formation in immature rat and mouse lung [264–269].”

“null mutant mice, a requirement for RA in pancreatic development has been proposed based on studies in RALDH null mutant mice [271,272] and in several other organisms in which retinoid signaling is deficient or inhibited, including Xenopus, zebrafish, chick, and quail [273–276].”

“family (A1, B1 and C1) [17–23].”

“A number of eye defects in RALDH3 and RALDH1/3 compound mutants [134,135,178] are also similar to those observed in late VAD rat embryos.”

“Retinol-binding protein (RBP or RBP4) carries the majority of retinol in the circulation [25], and a membrane receptor, STRA6, binds to RBP to enable efficient retinol uptake by a number of cells [26].”

“ureteric openings and other genitourinary tract defects have been reported in VAD rat fetuses [67,91].”

“Recognition of the importance of vitamin A in eye development first came from the experiments of Hale in which piglets from deficient mothers were born blind [86,87].”

“In vitamin A deficiency, the transition from A to A1 spermatogonia is blocked [42–44].”

“the diverse range of nerves and craniofacial structures essential to hindbrain function [161].”

“Early work in the laboratories of Wolbach and Howe as well as Mason showed that in vitamin A deficiency, the epithelia of the epididymis, prostate, and seminal vesicle is replaced with stratified squamous keratinizing epithelium, and spermatogenesis ceases [2,38].”

“reports that exogenous RA can stimulate alveoli formation in immature rat and mouse lung [264–269].”

“Adh 1, 3 and 4 enzyme family members are also expressed in developing embryos [126,127], however, mutation does not result in embryo lethality [128,129].”

“developing hindbrain all include an important role for CYP26 family members in regulating the formation of waves or pulses of RA in this dynamic process [23,144,172,173].”

“When severe VAD is imposed in quail, the initiation of heart morphogenesis is disrupted [88,228,229].”

“VAD rat embryos generated by severely restricting the amount of RA fed to deficient mothers at the beginning of pregnancy results in a loss of posterior rhombomere segmentation, with a significant shortening of the hindbrain [65].”

“Recent work shows that RA generated by RALDH2 in stromal mesenchyme acts in paracrine fashion to activate RA-receptor signaling and Ret expression in ureteric bud cells [242].”

“Raldh2 is largely responsible for RA synthesis in the mesonephros, with some contribution from Raldh3 in the region of the mesonephric duct [71,80].”

“Both defects in RA signaling and RA treatment have been shown to affect the expression of PDX-1 [271,272,275,278] an essential regulator of early pancreas development required for the”

“In RALDH2 null mutants, the expression of Fgf8 mRNA in the primitive ectoderm (epiblast) is shifted anteriorly such that it enters the node ectoderm and neuroectoderm, and somite development is abnormal [170].”

“Recognition of the importance of vitamin A in eye development first came from the experiments of Hale in which piglets from deficient mothers were born blind [86,87].”

“RA is also linked to the promotion of neurite outgrowth [157,162].”

“5 [132,148,203], after which Raldh3 (also called V1 activity) is expressed in the ventral neural retina and pigmented neuroepithelium [134,204–206] and Raldh1 (also called ADH-2) is expressed in the dorsal retina from E9.”

“Within the normal tubule, the Sertoli cell is believed to generate RA by the action of Raldh1 [49,51,52], and possibly Raldh2 [50].”

“Inhibitors of RA synthesis and vitamin A deficiency inhibit limb outgrowth in the quail [285,286].”

“Later work showed that in the VAD rat testes, undifferentiated spermatogonia, Sertoli cells and a small number of preleptotene spermatocytes remain [39–41], whereas in the mouse,”

“This is followed by the later expression of Cyp26A1 in r2 and Cyp26C1 in r2 and r4 [18,21,139,144].”

“(Adapted from [77,78]).”

“RA has been proposed to play a role in patterning the developing limb by regulating the pattern of expression of genes such as Hand2 (activates SHH), Shh (patterns the anterior-to-posterior axis), and Meis1/2 (transcription factors that mark the proximal limb bud mesenchyme) [287,290–292].”

“5 [132,148,203], after which Raldh3 (also called V1 activity) is expressed in the ventral neural retina and pigmented neuroepithelium [134,204–206] and Raldh1 (also called ADH-2) is expressed in the dorsal retina from E9.”

“The first and rate-limiting step in the production of RA from retinol results from the action of cytosolic alcohol dehydrogenases (ADH) and microsomal retinol dehydrogenases (RDH) yielding all-trans retinaldehyde [13].”

“RA acting through the RAR is also necessary for the morphogenesis of other components of the respiratory tract including partitioning of the primitive foregut into oesophagus and trachea, and for the opening between the nasal and oropharyngeal cavities [67,131,209,256,258,261].”

“Raldh2 in the embryo, along with expression in the visceral endoderm (extraembryonic) is required for vascular development in both the embryo proper, as well as the yolk sac [150–152].”

“Cyp1B1 can also generate RA and is expressed at known sites of RALDH-independent retinoid signaling [16], however, null mutant mice for this gene are viable [137].”

“importance of the RAR in mediating the actions of RA in developing embryos [99,101,102].”

“This is followed by the later expression of Cyp26A1 in r2 and Cyp26C1 in r2 and r4 [18,21,139,144].”

“The Rars are widely expressed in development [100].”

“postnatal lethality if maintained for two generations on a VAD diet [129].”

“However, a recent report shows that female RALDH2 and RALDH2/3 knockout gonads express Stra8 and undergo meiosis in the absence of detectable RA activity as assessed using a β2-RARE-lacZ (RARE-lacZ) reporter [74].”

“The rhombomere-specific expression pattern of the Cyp26 mRNAs led to the proposal that boundaries of RA activity are created by their expression [23,141,171] (Figure 4B).”

“5 [132,148,203], after which Raldh3 (also called V1 activity) is expressed in the ventral neural retina and pigmented neuroepithelium [134,204–206] and Raldh1 (also called ADH-2) is expressed in the dorsal retina from E9.”

“Nervous system, cardiovascular, and axial patterning defects result from early deficiency [63–66,96], whereas a less well-developed nasal region,”

“One of the best-studied functions of RA is in the developing hindbrain where it contributes to the anteroposterior patterning of the neural plate [159].”

“of Tgfβ signaling [262].”

“RA generated from within the spinal cord is required for the differentiation of a subset of lateral motor column (LMC) neurons that extend axons into the limb [192,193].”

“Interestingly, both the levels and domains of Cyp26 gene expression in the developing embryo are affected by retinoid status, whereas the Raldhs are unaffected [121].”

“Similar defects in PPF development are seen in rat embryos treated with nitrofen and several other CDH-inducing teratogens that interfere with the synthesis of RA and RA signaling in vivo [253,254].”

“In 1946, Arens and van Dorp synthesized vitamin A acid (retinoic acid), and reported it was as potent as vitamin A in supporting the growth of VAD rats but could not be converted back to vitamin A [8–10].”

“member, DHRS3a, which catalyzes reduction of retinaldehyde to retinol serving as a RA-induced feedback inhibitor of RA biosynthesis [138].”

“5 in vitamin A-sufficient rat embryos, but it is abnormal in late VAD embryos [252].”

“Retinol-binding protein (RBP or RBP4) carries the majority of retinol in the circulation [25], and a membrane receptor, STRA6, binds to RBP to enable efficient retinol uptake by a number of cells [26].”

“Retinol-binding protein (RBP or RBP4) carries the majority of retinol in the circulation [25], and a membrane receptor, STRA6, binds to RBP to enable efficient retinol uptake by a number of cells [26].”

“should remain off [175].”

“Instead, Molotkova and colleagues propose that RA functions at later times in forebrain development, and provide evidence that RA generated by RALDH3 in the lateral ganglionic eminence is required for normal expression of the dopamine D2 receptor in the nucleus accumbens and medial striatum [180].”

“Expression of RARα is needed for differentiation of the spermatogonia during prepuberty [55].”

“reports that exogenous RA can stimulate alveoli formation in immature rat and mouse lung [264–269].”

“Using direct identification by HPLC, all-trans retinaldehyde is detected in embryos as early as the egg cylinder or pre-primitive streak stage, whereas RA is detected between the mid-primitive streak stage and the late allantoic bud stage [146].”

“endoderm of the yolk sac visceral wall surrounding the embryo, and after definitive placentation, in the yolk sac membranes as well as in the uterus (decidua basalis) [111,112].”

“Webbed digits have been described in compound RAR mutant mice due to a loss of apoptosis [209,294].”

“insufficient amounts of RA [68].”

“HPLC studies of embryonic tissues at later times confirm that all-trans retinol and RA are the primary retinoids detected, with retinol clearly the most abundant [153–155].”

“heart tube patterning and looping, chamber and outflow tract septation, ventricular trabeculation, cardiomyocyte differentiation and coronary vessel development [231–233].”

“mesodermal markers are expanded at the expense of those representative of the prospective neuroepithelium [149].”

“null mutant mice, a requirement for RA in pancreatic development has been proposed based on studies in RALDH null mutant mice [271,272] and in several other organisms in which retinoid signaling is deficient or inhibited, including Xenopus, zebrafish, chick, and quail [273–276].”

“Raldh2 in the embryo, along with expression in the visceral endoderm (extraembryonic) is required for vascular development in both the embryo proper, as well as the yolk sac [150–152].”

“Although primary neurulation occurs in both RALDH2 mutant mice and VAD chick and rat embryos [65,123,187], the”

“Induction of more posterior domains occurs by the actions of RA, Wnts and FGFs, with RA specifying the posterior hindbrain and cervical spinal cord [160].”

“, who found that axial retinoic acid signals played a permissive role in the induction of zebrafish pectoral fins [289].”

“The mechanism by which RA activates cell death is currently a subject of active investigation [294–297].”

“Recent work supports the conclusion that the vitamin A metabolite, RA, is needed both for adult male spermatogonial differentiation (transition to A1) and the entrance into meiosis [45–47].”

“Defects result from the loss of control of programmed cell death in this region, and by loss of RA-mediated Pitx2, Foxc1, Eya2 and Dkk2 expression, and subsequent loss of repression of Wnt/β-catenin signaling [134,135,212,214].”

“A number of eye defects in RALDH3 and RALDH1/3 compound mutants [134,135,178] are also similar to those observed in late VAD rat embryos.”

“Adh 1, 3 and 4 enzyme family members are also expressed in developing embryos [126,127], however, mutation does not result in embryo lethality [128,129].”

“developing hindbrain all include an important role for CYP26 family members in regulating the formation of waves or pulses of RA in this dynamic process [23,144,172,173].”

“Respiratory defects including left lung agenesis, bilateral lung hypoplasia, and agenesis of the esophagotracheal septum were described in early VAD syndrome embryos but were characterized as rare anomalies [90,95].”

“of RALDH2, murine forelimb buds do not develop and embryonic growth ceases prior to the stage when hindlimb buds are initiated [287,288].”

“mice; some have been found to be dispensable, while roles for others have been revealed when animals are fed a vitamin A-restricted diet [12,27,28].”

“A recent report shows that there is a relationship between low cord retinol and RBP levels and CDH in newborn infants [249].”

“The all-trans isomer of RA is the highest affinity endogenous ligand for the RAR [31].”

“5 [132,148,203], after which Raldh3 (also called V1 activity) is expressed in the ventral neural retina and pigmented neuroepithelium [134,204–206] and Raldh1 (also called ADH-2) is expressed in the dorsal retina from E9.”

“mice; some have been found to be dispensable, while roles for others have been revealed when animals are fed a vitamin A-restricted diet [12,27,28].”

“CYP26B1 is also required later in embryogenesis to maintain cells in an undifferentiated state [82].”

“RA acting through the RAR is also necessary for the morphogenesis of other components of the respiratory tract including partitioning of the primitive foregut into oesophagus and trachea, and for the opening between the nasal and oropharyngeal cavities [67,131,209,256,258,261].”

“Recent work in Xenopus shows that RA down regulates XRDH10 transcripts, and this may serve as an additional mechanism to regulate endogenous retinoid levels [125].”

“In the meninges covering the cortex, levels of Raldh2 increase in the mouse embryo from E13 to E14 onward, to a maximal level in the newborn brain [184].”

“Adh 1, 3 and 4 enzyme family members are also expressed in developing embryos [126,127], however, mutation does not result in embryo lethality [128,129].”

“Additionally, they found that the period during which supplementation with vitamin A was most important was from gestation through a postnatal age of 6 months [270].”

“character [139,140], however, individual CYP26B1 and CYP26C1 mutants develop normally [143,144].”

“RBP does not cross the placenta into the fetal circulation [113].”

“In the mouse, Raldh2 (also called V2 activity) is transiently expressed in the optic vesicle neuroepithelium at E8.”

“When NAV2 is knocked down, the neuroblastoma cell is no longer able to extend neurites in response to RA [201].”

“heart tube patterning and looping, chamber and outflow tract septation, ventricular trabeculation, cardiomyocyte differentiation and coronary vessel development [231–233].”

“Both defects in RA signaling and RA treatment have been shown to affect the expression of PDX-1 [271,272,275,278] an essential regulator of early pancreas development required for the”

“pontine nuclei [182].”

“Cardiac and aortic arch defects were observed as a part of the early vitamin A deficiency syndrome in rat embryos [93,94] and in RAR compound null mutant mouse embryos [98,102].”

“There is clear in vivo evidence that vitamin A is required for the normal onset of meiotic prophase in ovarian germ cells [79].”

“RA was also reported in chick to contribute to regionalization of the telencephalon along the dorsoventral axis, and RALDH3 produced by the head ectoderm was proposed as the retinoid source [179].”

“Similar defects in PPF development are seen in rat embryos treated with nitrofen and several other CDH-inducing teratogens that interfere with the synthesis of RA and RA signaling in vivo [253,254].”

“5 in the rat embryo, a time when the cardiac primordium has completed looping and the primitive vasculature is established, early cardiac and aortic arch defects are not observed [67].”

“showed that vitamin A is required in the male neonate for germ cells to enter the first round of spermatogenesis [83].”

“Recently, a number of genes including neuron navigator 2 (Nav2) and Nedd9 were discovered in a screen for RA-responsive genes in a neuroblastoma cell line that elaborates neurites in response to RA [198–200].”

“the conjunctival sac, folding of the retina, absence of the vitreous body and the presence of a fibrous retrolenticular membrane [67,104].”

“The main symptoms observed in case of deficiency of vitamin A are intrauterine and post-natal growth retardation and a large array of congenital malformations collectively referred to as the fetal “vitamin A deficiency syndrome”, which is well documented in animals (Clagett-Dame and Knutson, 2011).”