Key Points
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Retinoic acid (RA), the active form of vitamin A, is a small lipophilic molecule that acts as a signalling molecule in vertebrates by binding to nuclear receptors (heterodimers of RA receptors and retinoid X receptors; RAR–RXR) and regulating the transcriptional activity of various target genes.
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The distribution of RA is tightly controlled in embryonic tissues. Its synthesis from inactive precursors (retinol or beta-carotene) is mediated by retinaldehyde dehydrogenases 1 to 3 (RALDH1 to RALDH3), and a group of cytochrome P450s (the cytochrome P450 26 enzymes CYP26A1 to CYP26C1) trigger its tissue-specific catabolism. Both types of enzymes are often expressed according to mutually exclusive, complementary patterns.
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Although there is clear evidence that RA acts as a short-range signal across tissue layers, its role as a long-range, concentration-dependent morphogen has long been debated. Recent work provided evidence for a robust RA gradient in the prospective hindbrain of the zebrafish embryo, shaped by the fibroblast growth factor (FGF)-dependent control of CYP26A1 activity.
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Although the most anterior (prospective head) embryonic cells are initially protected from RA signalling by CYP26A1 and CYP26C1 activities, eventually RA is produced by RALDH2 and RALDH3 in the rostral forebrain neuroepithelium and surface ectoderm, and is necessary for proper growth and patterning of the embryonic forebrain and optic vesicle.
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During extension of the body axis, a caudal pool of progenitor and/or stem cells is maintained by FGF8 signalling, and RA produced by RALDH2 in differentiating mesodermal tissues (including the somites) acts in an antagonist manner, promoting neurogenesis and regulating ventral patterning genes in the prospective spinal cord. RA is also necessary for 'buffering' left–right asymmetric embryonic signals, thus ensuring a symmetrical progression of mesodermal segmentation, that is, somitogenesis.
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Various functions have been ascribed to RA with respect to heart development, recent work implicated it in the proper restriction of the cardiac progenitor cell pool in the early zebrafish embryo, and in the mouse in the formation and proper contribution of the 'second heart field' to the developing heart tube.
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Cross-talk between RA and other embryonic signals are being unravelled. Contrasting with the functional antagonism between RA and FGF during caudal axis extension, during organ outgrowth RA was often found to have a positive effect on the induction (or the maintenance of appropriate levels) of FGF(s) involved in these processes. RA is also indispensable for cells to efficiently respond to the sonic hedgehog (SHH) signal, probably by controlling some downstream effectors of this pathway.
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RA signalling has been detected in regions of the adult rodent brain containing neural stem cell niches, and some studies have correlated decreased RA levels with neurodegenerative diseases, such as amyotrophic lateral sclerosis, or Alzheimer disease. Retinoids are already used in therapy, and a better understanding of the effects of RA — in combination with other signalling factors — in stem cell populations might lead to novel therapeutic avenues.
Abstract
Retinoic acid (RA) has complex and pleiotropic functions during vertebrate development. Recent work in several species has increased our understanding of the roles of RA as a signalling molecule. These functions rely on a tight control of RA distribution within embryonic tissues through the combined action of synthesizing and metabolizing enzymes, possibly leading to diffusion gradients. Also important is the switching of nuclear receptors from a transcriptionally repressing state to an activating state. In addition, cross-talk with other key embryonic signals, especially fibroblast growth factors (FGFs) and sonic hedgehog (SHH), is being uncovered. Some of these functions could be maintained throughout the life of an organism to regulate cell-lineage decisions and/or the differentiation of stem cell populations, highlighting possibilities for regenerative medicine.
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Acknowledgements
The authors are indebted to P. Chambon for initiating much of the research described in this paper. Work in the authors' laboratories is supported by grants from the National Institutes of Health (R01 #HL070733) and American Heart Association (#0330265N) to K.N, and funding from the CNRS, INSERM, Université Louis Pasteur, and grants from the Agence Nationale pour la Recherche, Fondation pour la Recherche Médicale, and European Union (EVI-GENORET # LSHG-CT-2005-512036) to P.D.
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A substance that is active in pattern formation, the spatial concentration or activity of which varies and to which cells respond differently at different threshold concentrations.
- Homeobox gene
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(Hox gene). A member of the family of genes involved in patterning the animal body axis during development. In vertebrates, Hox genes are clustered together on defined chromosomes and their sequential expression (both over time and along the embryonic axis) is related to the position on the chromosome.
- Neural tube
-
A cylindrical structure formed by dorsal midline closure of the neural plate (the embryonic neuroepithelium), and that will give rise to the brain and the spinal cord.
- Mesoderm
-
One of the three embryonic germ layers that is generated during gastrulation. It is a mesenchymal cell population found between the embryonic ectoderm and endoderm, and its derivatives include the trunk skeleton, muscles, heart, dermis and various organ tissues.
- Visceral endoderm
-
An extra-embryonic tissue — unrelated to the definitive endoderm lineage — that nourishes the vertebrate embryo.
- Anophthalmia
-
Lack of eye development.
- Primitive streak
-
A longitudinal cleft formed on the surface of the amniote early embryo by a convergence of cells. At the onset of gastrulation, epiblast cells migrate towards and into the streak, and consequently acquire a mesodermal cell fate.
- Somites
-
Segmental structures, consisting of epithelial blocks of tissue surrounding a cavity called the somitocoele, which are formed sequentially in the paraxial (presomitic) mesoderm and give rise to the sclerotome (precursors of the axial skeleton) and dermomyotome (precursors of the dermis of the back and skeletal muscles).
- Morpholino
-
Chemically modified, antisense oligonucleotides that are mainly used in zebrafish and X. laevis to inhibit either the translation or splicing of mRNAs.
- Cytochrome p450
-
A member of the large family of haem-containing enzymes, usually acting as monooxygenases and involved in the metabolism of many endogenous and exogenous compounds, as well as in hormone biosynthesis and breakdown.
- Glaucoma
-
Pathological condition resulting from abnormally elevated pressure in the liquid that fills the anterior chamber of the eye (the aqueous humour).
- Teratogenic
-
A molecule that causes malformation of an embryo.
- Rhombomeres
-
Segmental units transiently found in the hindbrain neuroepithelium, that adopt distinct molecular and cellular properties, restrictions in cell mixing, and ordered domains of gene expression.
- Neurectoderm
-
Region of the definitive embryonic ectoderm that undergoes neural induction and forms a columnar neuroepithelium or neural plate.
- Mesenchyme
-
Describes populations of cells that are not part of an epithelial sheet. In the early embryo, most (although not all) mesenchymal cell populations are derived from the mesoderm.
- Gastrula
-
Vertebrate embryo at the gastrulation stage.
- Neurula
-
Vertebrate embryo at the neurulation (formation of the neural plate) stage.
- Frontonasal
-
Describes the anteriormost region of the embryonic face, in which nasal and ocular structures will develop.
- Axial mesendoderm
-
Midline embryonic cells prior to the segregation of mesoderm and definitive endoderm, these cells will give rise to the notochord and floor plate of the neural tube, and produce several molecules involved in neural induction or patterning, including SHH.
- Telencephalon
-
Rostral (anterior) region of the forebrain, which gives rise to most of the cerebral hemispheres, including the cerebral cortex.
- Optic vesicle
-
Evagination of the forebrain neuroectoderm, from which both the neural and pigmented layers or the retina will develop.
- Cardiac crescent
-
Paired, crescent-like cell populations in the anterior lateral mesoderm, which later fuse along the midline to form the embryonic heart tube.
- Sertoli cells
-
Columnar, somatic cells of the testis seminiferous epithelium, which are responsive to FSH (follicle-stimulating hormone; a pituitary hormone) and in turn produce various hormones and proteins, including glial cell derived neurotrophic factor (GDNF).
- Mesonephros
-
The mid-region of the embryonic kidney that arises within the intermediate mesoderm between the pronephros and the metanephros (the definitive kidney). The gonad develops on the medial surface of this transient tissue, which also contains the primordia for the male (mesonephric) and female (paramesonephric or Müllerian) sex ducts.
- Seminiferous tubules
-
Coiled tubes within the testis, containing an epithelium composed of somatic Sertoli cells and germ cells at various stages of differentiation.
- Spina bifida
-
A congenital malformation that is due to a lack of closure of the caudal region of the neural tube, resulting in a protrusion of the lumbosacral spinal cord outside of the body.
- Branchial arches
-
Also known as pharyngeal arches. A series of paired segmental structures that are positioned on either side of the developing pharynx and are composed of ectoderm, mesoderm and neural crest cells. In mammals, the branchial arches contribute to pharyngeal organs and to the connective, skeletal, neural and vascular tissues of the head and neck.
- Subventricular zone
-
A neurogenic region that lines the ventricles of the adult brain.
- Olfactory bulb
-
Rostralmost portion of the mammalian brain, which receives inputs from the sensory olfactory axons.
- Hippocampus
-
A neurogenic region of the forebrain that has important functions in learning and memory.
- Embryoid bodies
-
Cell aggregates formed when embryonic stem cells are grown in suspension culture, and in which various cell types can be induced according to the culture conditions.
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Niederreither, K., Dollé, P. Retinoic acid in development: towards an integrated view. Nat Rev Genet 9, 541–553 (2008). https://doi.org/10.1038/nrg2340
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DOI: https://doi.org/10.1038/nrg2340
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