Skip to main content
Article thumbnail
Location of Repository

Function of retinoic acid receptors during embryonic development

By Manuel Mark, Norbert B. Ghyselinck and Pierre Chambon


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

Topics: Review
Publisher: The Nuclear Receptor Signaling Atlas
OAI identifier:
Provided by: PubMed Central

Suggested articles


  1. (1996). A decade of molecular biology of retinoic acid receptors
  2. (2007). A membrane receptor for retinol binding protein mediates cellular uptake of vitamin
  3. (2003). A newborn lethal defect due to inactivation of retinaldehyde dehydrogenase type 3 is prevented by maternal retinoic acid treatment Proc Natl Acad Sci
  4. (2009). A transcriptionally silent RXR{α} supports early embryonic morphogenesis and heart development Proc Natl Acad Sci
  5. (1994). Activation function 2 (AF-2) of retinoic acid receptor and 9-cis retinoic acid receptor: presence of a conserved autonomous constitutive activating domain and influence of the nature of the response element on AF-2 activity
  6. (1953). An analysis of the syndrome of malformations induced by maternal vitamin A deficiency. Effects of restoration of vitamin A at various times during gestation
  7. (2001). An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids Proc Natl Acad Sci
  8. (2004). Anterior eye development and ocular mesenchyme: new insights from mouse models and human diseases
  9. (2005). Apoptosis induced by vitamin A signaling is crucial for connecting the ureters to the bladder
  10. (1992). Can genes be truly redundant?
  11. (1996). Cell-type and promoter-context dependent retinoic acid receptor (RAR) redundancies for RAR β 2 and Hoxa-1 activation in F9 and P19 cells can be artefactually generated by gene knockouts Proc Natl Acad Sci
  12. (2001). Cloning of a novel retinoic-acid metabolizing cytochrome P450, Cyp26B1, and comparative expression analysis with Cyp26A1 during early murine development
  13. (1996). Compound mutants for retinoic acid receptor (RAR) β and RAR α 1 reveal developmental functions for multiple RAR β isoforms
  14. (2005). Contribution of cellular retinol-binding protein type 1 to retinol metabolism during mouse development Dev Dyn
  15. (1998). Contribution of retinoic acid receptor β isoforms to the formation of the conotruncal septum of the embryonic heart
  16. (2005). Convergent proliferative response and divergent morphogenic pathways induced by epicardial and endocardial signaling in fetal heart development
  17. (2007). Coordination of symmetric cyclic gene expression during somitogenesis by Suppressor of Hairless involves regulation of retinoic acid catabolism
  18. (2007). CYP26A1 and CYP26C1 cooperatively regulate anterior-posterior patterning of the developing brain and the production of migratory cranial neural crest cells in the mouse
  19. (2003). Cyp26C1 encodes a novel retinoic acid-metabolizing enzyme expressed in the hindbrain, inner ear, first branchial arch and tooth buds during murine development Gene Expr Patterns
  20. (2003). Decreased embryonic retinoic acid synthesis results in a DiGeorge syndrome phenotype in newborn mice
  21. (1998). Defects in embryonic hindbrain development and fetal resorption resulting from vitamin A deficiency in the rat are prevented by feeding pharmacological levels of all-trans-retinoic acid
  22. (1937). Developmental abnormalities of the eye.
  23. (2005). Direct crossregulation between retinoic acid receptor {β} and Hox genes during hindbrain segmentation Development
  24. (2002). Distal ureter morphogenesis depends on epithelial cell remodeling mediated by vitamin A and Ret
  25. (2006). Distinct roles for retinoic acid receptors α and β in early lung morphogenesis
  26. (2009). DOI: 10.1621/nrs.07002 | Page 11 of 15 Review RAR and RXR functions in
  27. (2009). DOI: 10.1621/nrs.07002 | Page 12 of 15 Review RAR and RXR functions in
  28. (2009). DOI: 10.1621/nrs.07002 | Page 13 of 15 Review RAR and RXR functions in
  29. (1999). Embryonic retinoic acid synthesis is essential for early mouse post-implantation development
  30. (2001). Embryonic retinoic acid synthesis is essential for heart morphogenesis in the mouse Development
  31. (2002). Embryonic retinoic acid synthesis is required for forelimb growth and anteroposterior patterning in the mouse Development
  32. (1995). Endogenous distribution of retinoids during normal development and teratogenesis in the mouse embryo Dev Dyn
  33. (1998). Energy deprivation and a deficiency in downstream metabolic target genes during the onset of embryonic heart failure in RXRalpha-/- embryos
  34. (2002). Epicardial induction of fetal cardiomyocyte proliferation via a retinoic acid-inducible trophic factor
  35. (2005). Epicardial retinoid X receptor α is required for myocardial growth and coronary artery formation Proc Natl Acad Sci
  36. (2001). F9 embryocarcinoma cells: a cell autonomous model to study the functional selectivity of RARs and RXRs in retinoid signaling
  37. (1993). Function of retinoic acid receptor γ in the mouse
  38. (1994). Function of the retinoic acid receptors (RARs) during development (I). Craniofacial and skeletal abnormalities in RAR double mutants Development
  39. (1994). Function of the retinoic acid receptors (RARs) during development (II). Multiple abnormalities at various stages of organogenesis in RAR double mutants Development
  40. (2003). Functions of RARs and RXRs in vivo: Genetic dissection of the retinoid signaling pathway
  41. (1994). Genetic analysis of RXR α developmental function: convergence of RXR and RAR signaling pathways in heart and eye morphogenesis
  42. (2006). Genetic and pharmacological evidence that a retinoic acid cannot be the RXR-activating ligand in mouse epidermis keratinocytes
  43. (1997). Genetic evidence that the retinoid signal is transduced by heterodimeric RXR/RAR functional units during mouse development Development
  44. (2000). Growth, adipose, brain, and skin alterations resulting from targeted disruption of the mouse peroxisome proliferator-activated receptor β(δ)
  45. (1993). High postnatal lethality and testis degeneration in retinoic acid receptor α mutant mice Proc Natl Acad Sci
  46. (2001). Hindbrain patterning involves graded responses to retinoic acid signalling Development
  47. (2008). Impairing retinoic acid signalling in the neural crest cells is sufficient to alter entire eye morphogenesis
  48. (2006). In germ cells of mouse embryonic ovaries, the decision to enter meiosis precedes premeiotic DNA replication
  49. (1997). In vivo functional analysis of the Hoxa-1 3' retinoic acid response element (3'RARE) Development
  50. (2007). Inhibition of Tgf β signaling by endogenous retinoic acid is essential for primary lung bud induction Development
  51. (2002). Interdigital apoptosis and downregulation of BAG-1 expression in mouse autopods
  52. (2006). Is 9-cis-retinoic acid the endogenous ligand for the retinoic acid-X receptor?
  53. (1999). Key roles of retinoic acid receptors α and β in the patterning of the caudal hindbrain, pharyngeal arches and otocyst in the mouse Development
  54. (2007). Matthew-Wood syndrome is caused by truncating mutations in the retinol-binding protein receptor gene STRA6
  55. (1998). Mesectoderm is a major target of retinoic acid action
  56. (2000). Mice bearing deletions of retinoic acid receptors demonstrate reduced lung elastin and alveolar numbers
  57. (2007). Molecular dynamics of retinoic acid-induced craniofacial malformations: implications for the origin of gnathostome jaws
  58. (1992). Multiplicity generates diversity in the retinoic acid signalling pathways
  59. (2007). Mutations in STRA6 cause a broad spectrum of malformations including anophthalmia, congenital heart defects, diaphragmatic hernia, alveolar capillary dysplasia, lung hypoplasia, and mental retardation
  60. (1995). Nonsteroid nuclear receptors: what are genetic studies telling us about their role in real life?
  61. (2002). Novel retinoic acid generating activities in the neural tube and heart identified by conditional rescue of
  62. (2005). Pathways of vitamin A delivery to the embryo: insights from a new tunable model of embryonic vitamin A deficiency Endocrinology
  63. (2003). Patterning of forelimb bud myogenic precursor cells requires retinoic acid signaling initiated by
  64. (1993). Patterns of diversity in mammalian skull :The skull
  65. (1933). Pigs born without eyeballs
  66. (1999). PPAR γ is required for placental, cardiac, and adipose tissue development
  67. (2001). RARgamma and Cdx1 interactions in vertebral patterning
  68. (2007). RDH10 is essential for synthesis of embryonic retinoic acid and is required for limb, craniofacial, and organ development
  69. (1995). Reexpression of retinoic acid receptor (RAR) γ or overexpression of RAR α or RAR β in RAR γ-null F9 cells reveals a partial functional redundancy between the three RAR types Proc Natl Acad Sci
  70. (2000). Regulation of retinoic acid signaling during lung morphogenesis Development
  71. (1996). Retinal dysplasia and degeneration
  72. (2006). Retinaldehyde dehydrogenase 2 (RALDH2)-mediated retinoic acid synthesis regulates early mouse embryonic forebrain development by controlling FGF and sonic hedgehog signaling Development
  73. (2005). Retinoic acid coordinates somitogenesis and left-right patterning in vertebrate embryos
  74. (2003). Retinoic acid receptor-α regulates pulmonary alveolus formation in mice after, but not during, perinatal period
  75. (2000). Retinoic acid receptor-β: an endogenous inhibitor of the perinatal formation of pulmonary alveoli
  76. (2006). Retinoic acid regulates morphogenesis and patterning of posterior foregut derivatives
  77. (2006). Retinoic acid regulates sex-specific timing of meiotic initiation in mice
  78. (2000). Retinoic acid regulation of Cdx1: an indirect mechanism for retinoids and vertebral specification
  79. (2004). Retinoic acid signalling in the development of branchial arches
  80. (2005). Retinoic acid signalling links left-right asymmetric patterning and bilaterally symmetric somitogenesis in the zebrafish embryo
  81. (2000). Retinoic acid synthesis and hindbrain patterning in the mouse embryo Development
  82. (2004). Retinoic acid synthesis controlled by Raldh2 is required early for limb bud initiation and then later as a proximodistal signal during apical ectodermal ridge formation
  83. (2005). Retinoic acid-dependent eye morphogenesis is orchestrated by neural crest cells Development
  84. (2003). Retinoic acid-induced developmental defects are mediated by RARbeta/RXR heterodimers in the pharyngeal endoderm Development
  85. (2006). Retinoic-acid signalling in node ectoderm and posterior neural plate directs left-right patterning of somitic mesoderm
  86. (2003). Retinoid activation of retinoic acid receptor but not retinoid X receptor is sufficient to rescue lethal defect in retinoic acid synthesis Proc Natl Acad Sci
  87. (2006). Retinoid signaling determines germ cell fate in mice
  88. (2000). Retinoid signaling is essential for patterning the endoderm of the third and fourth pharyngeal arches Development
  89. (1999). Retinoids and mammalian development Int Rev Cytol
  90. (2007). Retinoids control anterior and dorsal properties in the developing forebrain
  91. (2003). Retinoids regulate the anterior expression boundaries of 5' Hoxb genes in posterior hindbrain
  92. (2003). Retinoids, alveolus formation, and alveolar deficiency: clinical implications
  93. (2007). Role of retinoic acid during forebrain development begins late when Raldh3 generates retinoic acid in the ventral subventricular zone
  94. (1997). Role of the retinoic acid receptor β (RARbeta) during mouse development
  95. (1995). Roles of retinoic acid receptors and of Hox genes in the patterning of the teeth and of the jaw skeleton
  96. (2001). Roles of retinoic acid receptors in early embryonic morphogenesis and hindbrain patterning Development
  97. (1994). RXR α mutant mice establish a genetic basis for vitamin A signaling in heart morphogenesis
  98. (1996). RXR γ null mice are apparently normal and compound RXR α +/-/RXR β -/-/RXR γ -/- mutant mice are viable Proc Natl Acad Sci
  99. (2000). RXRalpha overexpression in cardiomyocytes causes dilated cardiomyopathy but fails to rescue myocardial hypoplasia in RXRalpha-null fetuses
  100. (2001). Site- and time-specific gene targeting in the mouse
  101. (2000). Stage-dependent responses of the developing lung to retinoic acid signaling
  102. (1999). Stromal cells mediate retinoid-dependent functions essential for renal development Development
  103. (1995). Synergistic activation of retinoic acid (RA)-responsive genes and induction of embryonal carcinoma cell differentiation by an RA receptor α (RAR α)-, RAR β-, or RAR γ-selective ligand in combination with a retinoid X receptor-specific ligand
  104. (2001). Synergistic teratogenic effects induced by retinoids in mice by coadministration of a RARalphaor RARgamma-selective agonist with a RXR-selective agonist Toxicol Appl Pharmacol
  105. (2001). Systematic immunolocalization of retinoid receptors in developing and adult mouse eyes
  106. (2003). Targeted conditional somatic mutagenesis in the mouse: temporally-controlled knock out of retinoid receptors in epidermal keratinocytes
  107. (2000). Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis
  108. (1996). Targeted disruption of the peroxisome proliferator-activated receptor α gene,
  109. (1997). Temporally-regulated retinoic acid depletion produces specific neural crest, ocular and nervous system defects Development
  110. (2004). The evolution of the nuclear receptor superfamily
  111. (2000). The function of vitamin D receptor in vitamin
  112. (1998). The LXRs: a new class of oxysterol receptors
  113. (2000). The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism
  114. (2002). The phosphorylation site located in the A region of retinoic X receptor α is required for the antiproliferative effect of retinoic acid (RA) and the activation of RA target genes in F9 cells
  115. (2001). The retinoic acid-metabolizing enzyme, CYP26A1, is essential for normal hindbrain patterning, vertebral identity, and development of posterior structures
  116. (1994). The Retinoids. Biology, Chemistry and Medicine
  117. (1998). The RXRalpha ligand-dependent activation function 2 (AF-2) is important for mouse development Development
  118. (1998). The use of a retinoid receptor antagonist in a new model to study vitamin A-dependent developmental events
  119. (1993). Thinking about genetic redundancy
  120. (2003). Thyroid hormone receptors: lessons from knockout and knock-in mutant mice
  121. (1994). Transport and metabolism of vitamin
  122. (2001). Vitamin A controls epithelial/mesenchymal interactions through Ret expression
  123. (1997). Vitamin A deficiency and mutations of RXRalpha, RXRbeta and RARalpha lead to early differentiation of embryonic ventricular cardiomyocytes Development
  124. (2000). Vitamin A deficiency results in the dose-dependent acquisition of anterior character and shortening of the caudal hindbrain of the rat embryo

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.