The role of retinoic acid in embryonic and post-embryonic development

Abstract

Retinoic acid (RA) is the bioactive metabolite of vitamin A (retinol) which acts on cells to establish or change the pattern of gene activity. Retinol is converted to RA by the action of two types of enzyme, retinol dehydrogenases and retinal dehydrogenases. In the nucleus RA acts as a ligand to activate two families of transcription factors, the RA receptors (RAR) and the retinoid X receptors (RXR) which heterodimerize and bind to the upstream sequences of RA-responsive genes. Thus, in addition to the well-established experimental paradigm of depriving animals of vitamin A to determine the role of RA in embryonic and post-embryonic development, molecular biology has provided us with two additional methodologies: knockout the enzymes or the RAR and RXR in the mouse embryo. The distribution of the enzymes and receptors, and recent experiments to determine the endogenous distribution of RA in the embryo are described here, as well as the effects on the embryo of knocking out the enzymes and receptors. In addition, recent studies using the classical vitamin A-deprivation technique are described, as they have provided novel insights into the regions of the embryo which crucially require RA, and the gene pathways involved in their development. Finally, the post-embryonic or regenerating systems in which RA plays a part are described, i.e. the regenerating limb, lung regeneration, hair cell regeneration in the ear and spinal cord regeneration in the adult.

Retinoic acid induces prostatic bud formation

“…Wilson and co-workers (Wilson and Warkany, 1948;Wilson et al, 1953) described a syndrome resulting from maternal hypovitaminosis A in rats that included hypoplastic UGS, but the authors did not examine prostatic buds in these studies. Prostatic budding defects were not reported in mice deficient in any single RAR isoform (Maden, 2000) or in compound mutants (Luo et al, 1996), but functional redundancy among the RAR isoforms makes it impossible to exclude retinoid signaling from involvement in prostatic bud formation. Prostatic budding defects were not reported in targeted RXR␣ knockout mice , but the CRE-LOX system used to generate RXR␣-null mice depended on expression of a prostate gene promoter that was only expressed postnatally (probasin) and was not appropriate for analysis of prostatic budding during fetal development.…”

“…In support of this possibility, there are numerous examples of RA re-specifying positional identity of inductive mesenchyme during development. Exposure of presomitic mesoderm to exogenous RA modified somite size in developing chicken and quail embryos (Diez del Corral et al, 2003;Maden, 2000). In utero exposure to RA reduced distal limb bud mesenchymal cell proliferation, reduced digit number, and shortened long bones in the developing mouse autopod (Hayes and MorrissKay, 2001).…”

Hyperglycaemia potentiates the teratogenicity of retinoic acid in diabetic pregnancy in mice

“…Retinoic acid plays an essential role in many developmental processes [29]. Both an excess and a deficiency of retinoic acid result in an overlapping array of malformations that affect the same target organ systems in the offspring [30,31,32], showing that the concentration of retinoic acid needs to be tightly regulated for normal development.…”

Molecular Cloning and Characterization of Bovine CYP26A1 Promoter

“…RA is an important biological regulator of gene expression and is involved in the growth and development of the cells as well as cell death [21,25]. RA is also a critical regulator of embryo development [2,17,30] and RA generated anterior and posterior axis by acting as an intercellular signal during early embryonic stages [2,9]. Some RAs are now in uses in cosmetic ingredient as antioxidant in anti-aging products [27], and RAs are used in treating dermatological problems such as acne and wrinkles [20].…”