Abstract
Retinoic acid (RA) is a vitamin A-derived, non-peptidic, small lipophilic molecule that acts as ligand for nuclear RA receptors (RARs), converting them from transcriptional repressors to activators. The distribution and levels of RA in embryonic tissues are tightly controlled by regulated synthesis through the action of specific retinol and retinaldehyde dehydrogenases and by degradation via specific cytochrome P450s (CYP26s). Recent studies indicate that RA action involves an interplay between diffusion (morphogen-like) gradients and the establishment of signalling boundaries due to RA metabolism, thereby allowing RA to finely control the differentiation and patterning of various stem/progenitor cell populations. Here, we provide an overview of the RA biosynthesis, degradation and signalling pathways and review the main functions of this molecule during embryogenesis.
Highlights
Retinoic acid (RA) is derived from the liposoluble vitamin A
We review the main functions of retinoid signalling during early embryonic development, first referring to the developing hindbrain as a system that has been most extensively studied with respect to RA functions and for which recent studies have refined our knowledge of the control of RA activity during rhombomeric segmentation
Conclusions there has been tremendous progress in characterising the numerous developmental events regulated by the retinoid pathway, many gaps remain with respect to the underlying mechanisms of RA-mediated patterning
Summary
Retinoic acid (RA) is derived from the liposoluble vitamin A (retinol). Vitamin A has long been known to be indispensable for vision, as its derivative retinaldehyde (Fig. 1) acts as a lightsensitive molecule, the isomerisation of which triggers the phototransduction process in photoreceptor cells of the retina (reviewed by Parker and Crouch, 2010). We further review extensive work that, over the last few years, has investigated how RA acts on progenitor cell populations in structures as diverse as the embryonic forebrain, the branchial apparatus and foregut derivatives, the neural plate and the posterior mesoderm during embryonic axial elongation. Understanding these functions and the underlying molecular events is of great importance, as retinoids are widely used in therapy and in many protocols for differentiating primary cultures or cell lines [including embryonic stem (ES) cells] into specific lineages (see Box 1). In mammals, retinol-RBP4 is taken up by target tissues, and this uptake can be facilitated in some tissues by a transmembrane protein that is the product of the RA-inducible gene
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