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Mechanisms of retinoic acid signalling and its roles in organ and limb development

Key Points

  • Retinoic acid (RA) was first implicated as a signalling molecule on the basis of its teratogenic effects on limb patterning. Studies in chick using treatment with RA or RA receptor antagonists suggested a two-signal model for limb proximodistal patterning in which a proximal RA signal opposes a distal fibroblast growth factor (FGF) signal.

  • Genetic loss-of-function studies in mice confirmed a requirement for distal FGF but not proximal RA in limb proximodistal patterning, thus supporting a one-signal model in which distal FGFs alone control patterning. RA was found to promote forelimb initiation by repressing Fgf8 along the body axis before limb budding.

  • RA–FGF8 antagonism has also been found to be essential for somitogenesis and neurogenesis during body axis extension. RA directly represses caudal Fgf8 through an upstream retinoic acid response element.

  • Genetic loss of RA synthesis has identified several additional roles for RA signalling during organogenesis, including neuronal differentiation in the hindbrain and spinal cord, eye morphogenesis, differentiation of forebrain basal ganglia, heart development and spermatogenesis. The putative role of RA in these developmental processes has been backed up by the identification of target genes that both require RA for normal expression and have nearby functional retinoic acid response elements.

  • Understanding the mechanism of RA-mediated activation and repression during development will benefit efforts to obtain differentiated cell types that are useful in regenerative medicine.

Abstract

Retinoic acid (RA) signalling has a central role during vertebrate development. RA synthesized in specific locations regulates transcription by interacting with nuclear RA receptors (RARs) bound to RA response elements (RAREs) near target genes. RA was first implicated in signalling on the basis of its teratogenic effects on limb development. Genetic studies later revealed that endogenous RA promotes forelimb initiation by repressing fibroblast growth factor 8 (Fgf8). Insights into RA function in the limb serve as a paradigm for understanding how RA regulates other developmental processes. In vivo studies have identified RAREs that control repression of Fgf8 during body axis extension or activation of homeobox (Hox) genes and other key regulators during neuronal differentiation and organogenesis.

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Figure 1: RA signalling mechanism.
Figure 2: Genetic studies indicate that limb patterning does not require RA signalling but does require FGF signalling and RA degradation.
Figure 3: RA–Fgf8 antagonism regulates the initiation of forelimb budding.
Figure 4: Direct RA target genes that are required for normal body axis extension, anteroposterior patterning, neurogenesis and somitogenesis.
Figure 5: Diverse roles of RA in regulating mouse organogenesis.

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Acknowledgements

This work was funded by a US National Institutes of Health grant GM062848 (to G.D.).

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Glossary

RA receptors

(RARs). DNA-binding nuclear receptors that directly regulate transcription in response to binding of their ligand retinoic acid (RA).

RA response elements

(RAREs). DNA elements that bind to retinoic acid (RA) receptors.

Caudal progenitor zone

The posterior (caudal) region of vertebrate embryos, which contains axial stem cells and other progenitor cells that progressively differentiate to form the body axis.

Body axis extension

The progressive formation of vertebrate embryos in a head-to-tail direction.

Stylopod

The proximal element of the limb (that is, upper arm or leg).

Zeugopod

The middle element of the limb (that is, lower arm or leg).

Autopod

The distal element of the limb (that is, hand or foot).

Homeobox (Hox) gene

A cluster of homeobox genes essential for axial patterning that exhibit spatial and temporal collinear expression, with genes in the 3′ end of each cluster expressed earlier and more anterior (or proximal for limbs) than 5′ genes.

Blastema

A mass of proliferating mesenchymal and epithelial cells that is located at the distal tip of the limb after amputation.

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Cunningham, T., Duester, G. Mechanisms of retinoic acid signalling and its roles in organ and limb development. Nat Rev Mol Cell Biol 16, 110–123 (2015). https://doi.org/10.1038/nrm3932

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