SurveyRegulation of retinoic acid signaling in the embryonic nervous system: a master differentiation factor
Section snippets
Retinoic acid — a systemic hormone or a locally synthesized factor?
Retinoic acid (RA) can be regarded as an inexpensive, pharmacological agent that is commonly used for its ability to effect differentiation in a large array of cell lines [1], as well as for inducing expression of more than 300 proteins [1], [2]. However, endogenous RA is a precisely regulated factor that controls many aspects of embryonic development and adult function. RA binds to and activates transcriptional regulators of the nuclear receptor family that also includes the receptors for
Vitamin A is the nutritional source of RA
Vitamin A (retinol) is the transcriptionally inactive precursor of RA, and it is oxidized to the active acid via the retinaldehyde intermediate (Fig. 1). As described in Section 6, RA is known to be highly teratogenic; because retinol is an inactive precursor, however, it is generally not considered teratogenic [7] unless high doses of vitamin supplements are taken. From normal dietary sources, it would be unusual to obtain a hazardous quantity, even from the consumption of organs of retinol
RA synthesis and catabolism
The importance of the retinoid-metabolizing enzymes in embryonic development has only recently been fully appreciated. Previously the tissue distributions of the binding proteins and RA receptors were considered as the dominant mechanisms for retinoid patterning of the embryo. Much recent work has demonstrated the importance of the synthetic enzymes in the development of the eye [23], spinal cord [24], [25] and brain [26], [27]. Most significantly, of the knockouts of the different components
RA regulates gene transcription
RA regulates transcription via the activation of several members of the nuclear receptor superfamily, as has been extensively reviewed elsewhere [72], [73], [74]. Of the two classes of RA receptors, the RARs (alpha, beta or gamma) are activated by all-trans RA and 9-cis RA, and the RXRs (alpha, beta or gamma) only by 9-cis RA. The RA receptors bind to specific response elements as dimers. Both RARs and RXRs can bind to their response elements as homodimers; however transcription is activated
RA is a broad differentiation factor
Experiments with RA as a pharmacological agent have shown that it can promote the differentiation of a wide variety of progenitor cell lines. This applies to embryonal carcinoma cells such as P19, F9 and Ntera-2 [85], [86], [87], to hemopoietic precursors including acute promyelocytic cells and HL60 [88], as well as to neuronal precursors such as PC12 and LAN-5 cells [89], [90]. RA is equally effective in inducing the differentiation of primary stem-cell cultures derived from rat brains [91].
RA teratogenesis
The initial evidence that vitamin A is essential for embryonic development came from the manipulation of retinoid levels in experimental animals [158], [159]. Maternal hypervitaminosis A leads to a range of well-defined developmental abnormalities in the nervous system, which include congenital abnormalities of the eyes, neural crest and hindbrain and the cerebellar anlage [159]. In humans, RA has been found to be equal in its teratogenicity to thalidomide. Unfortunately, cases of RA
Retinoid disturbances and human disease
The only human disease known to result from a disruption of RA signaling is acute promyelocytic leukemia (APL), in which a chromosomal translocation results in a fusion protein consisting of RARalpha with one of several factors (PML, PLZF, NPM or NuMA) [163]. It has been suggested, though, that altered retinoid regulation may be linked to Parkinson’s disease and schizophrenia [164], [165]. The sensitivity of the human embryo to RA teratogenicity reveals the fragility of the embryo to
Acknowledgements
Our work described in this review was supported by NIH grants HD05575, HD01174 and EY01938.
References (178)
- et al.
Regulation of thyroid hormone metabolism during fetal development
Mol. Cell Endocrinol.
(1999) - et al.
Changing patterns of the retinoic acid system in the developing retina
Dev. Biol.
(1993) - et al.
Retinoids and mammalian development
Int. Rev. Cytol.
(1999) - et al.
Identification of a mechanism to localize generation of retinoic acid in rat embryos
Mech. Dev.
(1997) Biosynthesis and metabolism of retinoic acid: roles of CRBP and CRABP in retinoic acid: roles of CRBP and CRABP in retinoic acid homeostasis
J. Nut.
(1993)- et al.
Nuclear import of cellular retinoic acid-binding protein type I in mouse embryonic cells
Mech. Dev.
(1996) - et al.
Motor neuron-derived retinoid signaling specifies the subtype identity of spinal motor neurons
Cell
(1998) - et al.
Influence of the choroid plexus on cerebellar development: analysis of retinoic acid synthesis
Dev. Brain Res.
(1996) - et al.
Hox gene activation by retinoic acid
Trends Genet.
(1991) Alcohol dehydrogenase as a critical mediator of retinoic acid synthesis from vitamin A in the mouse embryo
J. Nutr.
(1998)
Retinoic acid synthesis in mouse embryos during gastrulation and craniofacial development linked to class IV alcohol dehydrogenase gene expression
J. Biol. Chem.
Identification of mouse liver aldehyde dehydrogenases that catalyze the oxidation of retinaldehyde to retinoic acid
Biochem. Pharmacol.
Biotransformation of all-trans-retinol and all-trans-retinal to all-trans-retinoic acid in rat conceptal homogenates
Biochem. Pharmacol.
A sensitive bioassay for enzymes that synthesize retinoic acid
Brain Res. Prot.
The 56 kDa androgen binding protein is an aldehyde dehydrogenase
Biochem. Biophys. Res. Commun.
Restricted expression and retinoic acid-induced downregulation of the retinaldehyde dehydrogenase type 2 (RALDH-2) gene during mouse development
Mech. Dev.
A sonic hedgehog-independent, retinoid-activated pathway of neurogenesis in the ventral spinal cord
Cell
Differential distribution of retinoic acid synthesis in the chicken embryo as determined by immunolocalization of the retinoic acid synthetic enzyme, RALDH-2
Dev. Biol.
A ventrodorsal GABA gradient in the embryonic retina prior to expression of glutamate decarboxylase
Neuroscience
Eph family receptors and their ligands distribute in opposing gradients in the developing mouse retina
Dev. Biol.
Participation of P450 3A enzymes in rat hepatic microsomal retinoic acid 4-hydroxylation
Arch. Biochem. Biophys.
Participation of CYP2C8 in retinoic acid 4-hydroxylation in human hepatic microsomes
Biochem. Pharmacol.
Dynamic patterns of retinoic acid synthesis and response in the developing mammalian heart
Dev. Biol.
The retinoid signaling pathway: molecular and genetic analyses
Semin. Cell Biol.
The RXR heterodimers and orphan receptors
Cell
Coactivator and corepressor complexes in nuclear receptor function
Curr. Opin. Genet. Dev.
Genetic analysis of RXR alpha developmental function: convergence of RXR and RAR signaling pathways in heart and eye morphogenesis
Cell
Developmental roles of the retinoic acid receptors
J. Steroid Biochem. Mol. Biol.
Leukemia cell lines: in vitro models for the study of acute promyelocytic leukemia
Leuk. Res.
Cholinergic differentiation of clonal rat pheochromocytoma cells (PC12) induced by retinoic acid: increase of choline acetyltransferase activity and decrease of tyrosine hydroxylase activity
Brain Res.
Differentiation of LA-N-5 neuroblastoma cells into cholinergic neurons: methods for differentiation, immunohistochemistry and reporter gene introduction
Brain Res. Brain Res. Protoc.
New prospects for human stem-cell therapy in the nervous system
Trends Neurosci.
A direct repeat in the cellular retinol-binding protein type II gene confers differential regulation by RXR and RAR
Cell
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
The HNF-3alpha transcription factor is a primary target for retinoic acid action
Exp. Cell Res.
Identification of a retinoic acid responsive enhancer 3′ of the murine homeobox gene Hox-1.6
Mech. Dev.
Cellular biology and biochemistry of the retinoids
Impaired retinal function and vitamin A availability in mice lacking retinol-binding protein
EMBO. J.
Gender-specific steroid metabolism in neural differentiation
Cell Mol. Neurobiol.
Plasma delivery of retinoic acid to tissues in the rat
J. Biol. Chem.
Teratogencity of vitamin A and retinoids
Safety of vitamin A: recent results
Int. J. Vitam. Nutr. Res.
Absorption of vitamin A
A retinol-binding protein receptor-mediated mechanism for uptake of vitamin A to postimplantation rat embryos
Biol. Reprod.
Retinol-binding protein and transthyretin mRNA levels in visceral yolk sac and liver during fetal development in the rat
Proc. Natl. Acad. Sci. USA
Retinol bound to cellular retinol-binding protein is a substrate for cytosolic retinoic acid synthesis
J. Biol. Chem.
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.
Physical and functional interactions between cellular retinoic acid binding protein II and the retinoic acid-dependent nuclear complex
Mol. Cell. Biol.
Retinoic acid biosynthesis and metabolism
FASEB. J.
Cellular retinol-binding protein I is essential for vitamin A homeostasis
EMBO. J.
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