Retinoic acid signalling in the development of branchial arches
Introduction
Branchial arches (BAs) are transient bulges of the embryonic oropharyngeal region (Figure 1a–c), giving rise to specific sets of adult tissue derivatives (see Table 1 for examples), the formation of which critically depends upon retinoic acid (RA). This active metabolite of vitamin A (retinol) is indispensable for patterning the anteroposterior body axis, for morphogenesis and organogenesis [1•]. Its tissue distribution results from the balancing activities of RA-synthesizing enzymes (including retinaldehyde dehydrogenases RALDH1 to RALDH4), and RA-catabolizing cytochrome P450 hydroxylases (CYP26A1, B1 and C1) 2., 3.. The pleiotropic effects of RA are mediated through ligand-dependent transcriptional regulators belonging to the nuclear receptor superfamily: the retinoic acid receptors (RARα, β and γ isotypes) and the retinoid X receptors (RXRα, β and γ isotypes) that bind as RXR/RAR heterodimers to response elements located in RA-responsive genes. A genetic dissection, through targeted mutagenesis performed in the mouse, has revealed that RXRα/RAR(α, β and γ) heterodimers represent the main functional units of the RA signalling pathway during embryonic development [1•].
Section snippets
Retinoid signalling mediated by RXRα/RAR-heterodimers is indispensable for the development of branchial arches 3–6
When analyzed between embryonic day (E) 9.5 and E 10.5, mouse embryos carrying targeted inactivation of RARα and RARβ (RARαβ-null mutants), or RARα and RARγ (RARαγ-null mutants) genes, display hypoplasia of BA3–6 and their corresponding branchial pouches (BPs) 4., 5.. Similar hypoplasia of BA3 and BP3 is observed in vitamin-A-deficient (VAD) quails and rats 6., 7., 8., in RALDH2-null and hypomorphic (RALDH2hypo) mutant mice 9., 10., 11., 12.•, and in mice expressing a dominant negative (dn)
The development of branchial arches 1–2 involves retinoic acid-dependent cellular and molecular mechanisms that are distinct from those in caudal branchial arches
BA1 is never missing under experimental conditions resulting in blocks in RA signalling, and hypoplasia of BA1 only occurs in a context of general embryonic growth retardation caused by RA deprivation 7., 9.. However, several BA1-derivatives cannot develop properly when RA signalling is impaired. For instance, morphogenesis of molars, which are derived from BA1 ectoderm and mesenchyme, clearly requires RA (Figure 3a,b). Similarly, atavistic modifications of chondrogenesis in BA1 of RARα-null
The teratogenic effects of retinoic acid excess and deficiency involve distinct cellular and molecular mechanisms in the oropharyngeal region
Treatments with pharmacological doses of RA, or other retinoids, during pregnancy causes multiple malformations which are receptor-mediated, and whose nature depends on the time of RA administration. In humans, intake of isotretinoin (13-cis RA) during gastrulation and early organogenesis (gestational weeks 3–5) results in a spectrum of congenital malformations collectively referred to as RA-induced embryopathy (RAE) [46]. In animal models of RAE, fusion and hypoplasia of the first two BA
Conclusions
Malformations induced by excess RA resemble those generated upon silencing RA-dependent pathways. For instance, a CATCH22-like spectrum of defects is recapitulated in mouse fetuses exposed to excess vitamin A [51]. Such similarities have popularized the idea that both RA excess and RA deficiency impair developmental processes by disrupting identical mechanisms. With respect to the early development of the oropharyngeal region, this is, however, clearly not the case for the following reasons.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This review is dedicated to the memory of Professor Jean-Victor Ruch. We thank all past and current members of the group for exciting discussions. We apologize that, because of strict space limitations, many primary references could not be cited directly. They will be found in reviews cited in the text. This work was supported by funds from the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), the Collège de France, and
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