The developing mammalian embryo is entirely dependent on the maternal circulation for its supply of retinoids (vitamin A and its metabolites). The mechanisms through which mammalian developing tissues maintain adequate retinoid levels in the face of suboptimal or excessive maternal dietary vitamin A intake have not been established. We investigated the role of retinyl ester formation catalyzed by lecithin:retinol acyltransferase (LRAT) in regulating retinoid homeostasis during embryogenesis. Dams lacking both LRAT and retinol-binding protein (RBP), the sole specific carrier for retinol in serum, were maintained on diets containing different amounts of vitamin A during pregnancy. We hypothesized that the lack of both proteins would make the embryo more vulnerable to changes in maternal dietary vitamin A intake. Our data demonstrate that maternal dietary vitamin A deprivation during pregnancy generates a severe retinoid-deficient phenotype of the embryo due to the severe retinoid-deficient status of the double mutant dams rather than to the lack of LRAT in the developing tissues. Moreover, in the case of excessive maternal dietary vitamin A intake, LRAT acts together with Cyp26A1, one of the enzymes that catalyze the degradation of retinoic acid, and possibly with STRA6, the recently identified cell surface receptor for retinol-RBP, in maintaining adequate levels of retinoids in embryonic and extraembryonic tissues. In contrast, the pathway of retinoic acid synthesis does not contribute significantly to regulating retinoid homeostasis during mammalian development except under conditions of severe maternal retinoid deficiency. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe crucial role played by vitamin A in embryonic development has long been known (1-5). Both embryonic vitamin A deficiency and excess give rise to fetal death or to a spectrum of congenital defects, in a dose and developmental stage-dependent manner (4). Vitamin A exerts its functions through retinoic acid, a lipid-soluble hormone that regulates the expression of many target genes through receptor-mediated events (6). Retinoic acid is generated from retinol (vitamin A alcohol) through two oxidative enzymatic reactions via retinaldehyde (7). When retinoid signaling needs to be turned off, retinoic acid is enzymatically catabolized into more polar products such as 4-hydroxy retinoic acid or 4-oxo retinoic acid. This oxidation is achieved by the action of several cytochrome P450 enzymes, including Cyp26A1, Cyp26B1, and Cyp26C1 (8-10).Because there is no de novo fetal synthesis of vitamin A, mammalian developing tissues are entirely dependent on maternal circulating retinoids (vitamin A and its metabolites) that reach the embryo through the maternal-fetal barrier, i.e. the placenta (11). Retinol bound to its specific transport protein, retinol-binding protein (RBP), 5 is the major form of vitamin A in the fasting circulation where it is secreted from the liver, the main body store of vitamin A. However, upon dieta...

The mammalian embryo relies on maternal circulating retinoids (vitamin A derivatives) for development. β-Carotene is the major human dietary provitamin A. β-Carotene-15,15'-oxygenase (CMOI) has been proposed as the main enzyme generating retinoid from β-carotene in vivo. CMOI is expressed in embryonic tissues, suggesting that β-carotene provides retinoids locally during development. We performed loss of CMOI function studies in mice lacking retinol-binding protein (RBP), an established model of embryonic vitamin A deficiency (VAD). We show that, unexpectedly, lack of CMOI in the developing tissues further exacerbates the severity of VAD and thus the embryonic malformations of RBP(-/-) mice. Since β-carotene was not present in any of the mouse diets, we unveiled a novel action of CMOI independent from its β-carotene cleavage activity. We also show for the first time that CMOI exerts an additional function on retinoid metabolism by influencing retinyl ester formation via modulation of lecithin:retinol acyltransferase (LRAT) activity, at least in developing tissues. Finally, we demonstrate unequivocally that β-carotene can serve as an alternative vitamin A source for the in situ synthesis of retinoids in developing tissues by the action of CMOI.

During pregnancy, parathyroid hormone-related protein (PTHrP) is one of many growth factors that play important roles to promote fetal growth and development, including stimulation of placental calcium transport. Angiotensin II, acting through the AT(1a) receptor, is also known to promote placental growth. We examined the effects of bilateral uterine artery and vein ligation (restriction), which mimics placental insufficiency in humans, on growth, intrauterine PTHrP, placental AT(1a), and pup calcium. Growth restriction was surgically induced on day 18 of pregnancy in Wistar-Kyoto female rats by uterine vessel ligation. Uteroplacental insufficiency reduced fetal body weight by 15% and litter size (P < 0.001) compared with the control rats with no effect on placental weight or amniotic fluid volume. Uteroplacental insufficiency reduced placental PTHrP content by 46%, with increases in PTHrP (by 2.6-fold), parathyroid hormone (PTH)/PTHrP receptor (by 11.6-fold), and AT(1a) (by 1.7-fold) relative mRNA in placenta following restriction compared with results in control (P < 0.05). There were no alterations in uterine PTHrP and PTH/PTHrP receptor mRNA expression. Maternal and fetal plasma PTHrP and calcium concentrations were unchanged. Although fetal total body calcium was not altered, placental restriction altered perinatal calcium homeostasis, as evidenced by lower pup total body calcium after birth (P < 0.05). The increased uterine and amniotic fluid PTHrP (P < 0.05) may be an attempt to compensate for the induced impaired placental function. The present study demonstrates that uteroplacental insufficiency alters intrauterine PTHrP, placental AT(1a) expression, and perinatal calcium in association with a reduction in fetal growth. Uteroplacental insufficiency may provide an important model for exploring the early origins of adult diseases.

The effects of high glucose on PTC proliferation, reduced apoptosis and increased NHE3 mRNA levels are mediated by EGFR-dependent up-regulation of SGK-1.

The requirement of the developing mammalian embryo for retinoic acid is well established. Retinoic acid, the active form of vitamin A, can be generated from retinol and retinyl ester obtained from food of animal origin, and from carotenoids, mainly β-carotene, from vegetables and fruits. The mammalian embryo relies on retinol, retinyl ester and β-carotene circulating in the maternal bloodstream for its supply of vitamin A. The maternal-fetal transfer of retinoids and carotenoids, as well as the metabolism of these compounds in the developing tissues are still poorly understood. The existing knowledge in this field has been summarized in this review in reference to our basic understanding of the transport and metabolism of retinoids and carotenoids in adult tissues. The need for future research on the metabolism of these essential lipophilic nutrients during development is highlighted.

These findings suggest that the EGF-EGF receptor (EGFR) axis has a significant role in the development of early diabetes-related kidney growth. The impact of EGFR inhibition on the later development of renal dysfunction, however, remains to be determined.

Retinoic acid is a biologically active derivative of vitamin A that is indispensable for inner ear development. The normal function of retinoic acid is achieved only at optimal homeostatic concentrations, with an excess or deficiency in retinoic acid leading to inner ear dysmorphogenesis. We present an overview of the role of retinoic acid in the developing mammalian inner ear, discussing both how and when retinoic acid may act to critically control a program of inner ear development. Molecular mechanisms of otic teratogenicity involving two members of the fibroblast growth factor family, FGF3 and FGF10, and their downstream targets, Dlx5 and Dlx6, are examined under conditions of both retinoic acid excess and deficiency. We term the effect of too little or too much retinoic acid on FGF/Dlx signaling a Goldilocks phenomenon. We demonstrate that in each case (retinoic acid excess, retinoic acid deficiency), retinoic acid can directly affect FGF3/FGF10 signaling within the otic epithelium, leading to downregulated expression of these essential signaling molecules, which in turn, leads to diminution in Dlx5/Dlx6 expression. Non-cell autonomous affects of the otic epithelium subsequently occur, altering transforming growth factor beta (TGFβ) expression in the neighboring periotic mesenchyme and serving as a putative explanation for retinoic acid-mediated otic capsule defects. We conclude that retinoic acid coordinates inner ear morphogenesis by controlling an FGF/Dlx signaling cascade, whose perturbation by deviations in local retinoid concentrations can lead to inner ear dysmorphogenesis.

The human diet contains β-carotene as the most abundant precursor of vitamin A, an essential nutrient for embryogenesis. Our laboratory previously showed the importance of β-carotene metabolism via β-carotene-15,15'-oxygenase (CMOI) to support mouse embryonic development. However, the mechanisms regulating embryonic acquisition and utilization of β-carotene from the maternal circulation via placenta remain unknown. We used wild-type (WT) and Lrat(-/-)Rbp(-/-) (L(-/-)R(-/-)) mice, the latter being a model of marginal vitamin A deficiency. Pregnant dams, fed a nonpurified diet sufficient in vitamin A throughout life, were i.p. supplemented with β-carotene or vehicle at 13.5 d postcoitum (dpc). Effects of this acute maternal supplementation on retinoid and β-carotene metabolism in maternal (serum, liver) and developing tissues (placenta, yolk sac, embryo) were investigated at 14.5 dpc. We showed that, upon supplementation, placental β-carotene concentrations were greater in L(-/-)R(-/-) than in WT mice. However, the retinoid (retinol and retinyl ester) concentrations remained unchanged in placenta (and in all other tissues analyzed) of both genotypes upon β-carotene administration. We also showed that upon a single i.p. β-carotene supplementation, placental LDL receptor-related protein (Lrp1) mRNA expression was lower in WT mice, and embryonic CmoI mRNA expression was greater in L(-/-)R(-/-) mice. Together, these data suggest a potential role of LRP1 in mediating the uptake of β-carotene across the placenta and that even a marginally impaired maternal vitamin A status may influence uptake and utilization of β-carotene by the placenta and the embryo.