Early retinoic acid signaling organizes the body axis and defines domains for the forelimb and eye.

Abstract

All-trans RA (ATRA) is a small molecule derived from retinol (vitamin A) that directly controls gene expression at the transcriptional level by serving as a ligand for nuclear ATRA receptors. ATRA is produced by ATRA-generating enzymes that convert retinol to retinaldehyde (retinol dehydrogenase; RDH10) followed by conversion of retinaldehyde to ATRA (retinaldehyde dehydrogenase; ALDH1A1, ALDH1A2, or ALDH1A3). Determining what ATRA normally does during vertebrate development has been challenging as studies employing ATRA gain-of-function (RA treatment) often do not agree with genetic loss-of-function studies that remove ATRA via knockouts of ATRA-generating enzymes. In mouse embryos, ATRA is first generated at stage E7.5 by ATRA-generating enzymes whose genes are first expressed at that stage. This article focuses upon what ATRA normally does at early stages based upon these knockout studies. It has been observed that early-generated ATRA performs three essential functions: (1) activation of genes that control hindbrain and spinal cord patterning; (2) repression of Fgf8 in the heart field and caudal progenitors to provide an FGF8-free region in the trunk essential for somitogenesis, heart morphogenesis, and initiation of forelimb fields; and (3) actions that stimulate invagination of the optic vesicle to form the optic cup.