Retinoic acid in development: towards an integrated view

Retinoic acid (RA), the active form of vitamin A, is a small lipophilic molecule that acts as a signalling molecule in vertebrates by binding to nuclear receptors (heterodimers of RA receptors and retinoid X receptors; RAR–RXR) and regulating the transcriptional activity of various target genes.Get more news about retinoic acid,you can vist our website!

The distribution of RA is tightly controlled in embryonic tissues. Its synthesis from inactive precursors (retinol or beta-carotene) is mediated by retinaldehyde dehydrogenases 1 to 3 (RALDH1 to RALDH3), and a group of cytochrome P450s (the cytochrome P450 26 enzymes CYP26A1 to CYP26C1) trigger its tissue-specific catabolism. Both types of enzymes are often expressed according to mutually exclusive, complementary patterns.

Although there is clear evidence that RA acts as a short-range signal across tissue layers, its role as a long-range, concentration-dependent morphogen has long been debated. Recent work provided evidence for a robust RA gradient in the prospective hindbrain of the zebrafish embryo, shaped by the fibroblast growth factor (FGF)-dependent control of CYP26A1 activity.

Although the most anterior (prospective head) embryonic cells are initially protected from RA signalling by CYP26A1 and CYP26C1 activities, eventually RA is produced by RALDH2 and RALDH3 in the rostral forebrain neuroepithelium and surface ectoderm, and is necessary for proper growth and patterning of the embryonic forebrain and optic vesicle.

During extension of the body axis, a caudal pool of progenitor and/or stem cells is maintained by FGF8 signalling, and RA produced by RALDH2 in differentiating mesodermal tissues (including the somites) acts in an antagonist manner, promoting neurogenesis and regulating ventral patterning genes in the prospective spinal cord. RA is also necessary for 'buffering' left–right asymmetric embryonic signals, thus ensuring a symmetrical progression of mesodermal segmentation, that is, somitogenesis.

Various functions have been ascribed to RA with respect to heart development, recent work implicated it in the proper restriction of the cardiac progenitor cell pool in the early zebrafish embryo, and in the mouse in the formation and proper contribution of the 'second heart field' to the developing heart tube.

Cross-talk between RA and other embryonic signals are being unravelled. Contrasting with the functional antagonism between RA and FGF during caudal axis extension, during organ outgrowth RA was often found to have a positive effect on the induction (or the maintenance of appropriate levels) of FGF(s) involved in these processes. RA is also indispensable for cells to efficiently respond to the sonic hedgehog (SHH) signal, probably by controlling some downstream effectors of this pathway.

RA signalling has been detected in regions of the adult rodent brain containing neural stem cell niches, and some studies have correlated decreased RA levels with neurodegenerative diseases, such as amyotrophic lateral sclerosis, or Alzheimer disease. Retinoids are already used in therapy, and a better understanding of the effects of RA — in combination with other signalling factors — in stem cell populations might lead to novel therapeutic avenues.