Function of retinoic acid receptors during embryonic development
Open accessAbstract
Retinoids, the active metabolites of vitamin A, regulate complex gene networks involved in vertebrate morphogenesis, growth, cellular differentiation and homeostasis. Studies performed in vitro, using either acellular systems or transfected cells, have shown that retinoid actions are mediated through heterodimers between the RAR and RXR nuclear receptors. However, in vitro studies indicate what is possible, but not necessarily what is actually occurring in vivo, because they are performed under non-physiological conditions. Therefore, genetic approaches in the animal have been be used to determine the physiological functions of retinoid receptors. Homologous recombination in embryonic stem cells has been used to generate germline null mutations of the RAR- and RXR-coding genes in the mouse. As reviewed here, the generation of such germline mutations, combined with pharmacological approaches to block the RA signalling pathway, has provided genetic evidence that RAR/RXR heterodimers are indeed the functional units transducing the RA signal during prenatal development. However, due to (i) the complexity in "hormonal" signalling through transduction by the multiple RARs and RXRs, (ii) the functional redundancies (possibly artefactually generated by the mutations) within receptor isotypes belonging to a given family, and (iii) in utero or early postnatal lethality of certain germline null mutations, these genetic studies have failed to reveal all the physiological functions of RARs and RXRs, notably in adults. Spatio-temporally-controlled somatic mutations generated in given cell types/tissues and at chosen times during postnatal life, will be required to reveal all the functions of RAR and RXR throughout the lifetime of the mouse.
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RARs work as ligand-dependent regulators of transcription and transduce the RA signal in vivo as heterodimers with RXR.
“the so-called retinoic acid receptors (RAR), which work as ligand-dependent regulators of transcription and transduce the RA signal in vivo as heterodimers with retinoic X receptors (RXR) ( 5,6 ).”
From Vitamin A and retinoid signaling: genomic and nongenomic effects (2013) · cites this paper as [6]
RA binds and activates RARs.
“Today, it is well admitted that RA binds and activates RARs.”
From Vitamin A and retinoid signaling: genomic and nongenomic effects (2013) · cites this paper as [6]
RA mobilizes to the nucleus through binding to small intracellular lipid-binding proteins.
“Basically, RA mobilizes to the nucleus through binding to small intracellular lipid-binding proteins.”
From Vitamin A and retinoid signaling: genomic and nongenomic effects (2013) · cites this paper as [6]
The Introduction discusses RA-binding transcriptional regulators, and the Conclusions and perspectives section discusses RAR/RXR heterodimers transducing RA signals. Neither passage says RA reaches the nucleus by binding small intracellular lipid-binding proteins; searches for those proteins and nuclear transport found no supporting passage in our copy. (LLM, conf=0.72)
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Self-citationDistinct roles for retinoic acid receptors alpha and beta in early lung morphogenesis.
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Self-citationStage-dependent responses of the developing lung to retinoic acid signaling.
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Self-citationDirect crossregulation between retinoic acid receptor β and Hox genes during hindbrain segmentation
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Self-citationTargeted Disruption of the Peroxisome Proliferator—Activated Receptor α Gene, PPARα
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- Authors
- Mark, M., Ghyselinck, N. B., & Chambon, P.
- Affiliations
- Institut de génétique et de biologie moléculaire et cellulaire (FR)
- Département de Génomique Fonctionnelle, Strasbourg, France
- Collège de France (FR)
- Corresponding author
- Ghyselinck, Norbert B.
- Chambon, Pierre
- Venue
- Nuclear Receptor Signaling
- Publisher
- SAGE Publications
- Published
- 2009-01
- Volume
- 7
- Issue
- 1
- Pages
- e002-e002
- ISSN
- 1550-7629 (ISSN-L)
- PMC
- PMC2670431
- OpenAlex
- W2134977065
- Cited by
- 363
- References
- 133
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 12 · 2023: 12 · 2022: 12 · 2021: 21 · 2020: 13 · 2019: 23 · 2018: 11 · 2017: 23 · 2016: 22 · 2015: 26 · 2014: 34 · 2013: 27 · 2012: 36
- FWCI
- 3.06
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nuclear Receptor Signaling (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, other-oa)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Keywords
- retinoic acid receptor, retinoid X receptor, retinoic acid signaling, embryonic development, RAR/RXR heterodimers, receptor redundancy, morphogenesis, cell differentiation
- MeSH terms
- Animals, Female, Humans, Mutation, Pregnancy, Vitamin A Deficiency, Signal Transduction, Receptors, Retinoic Acid, Embryonic Development, Retinoid X Receptors, Mice
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