Retinoic acid acts during peri-implantational development to alter axial and brain formation

All-trans retinoid acid (RA) induces a stereotypic spectrum of stage-specif ic malformations in vertebrate conceptuses. The present work evaluated the anatomic and biochemical effects of exposure to RA in mouse embryos at a pe ri-implantational stage of development - gestational day (GD) 5. The RA rec eptors (RARs) beta and gamma, the retinoid X receptors (RXRs) alpha and bet a, and the cellular retinoid acid binding proteins (CRABPs) I and II were d etected by RT-PCR in both control and treated individual GD 5 decidua/embry o complexes 3 h after RA injection, indicating the presence of the mRNAs co ding for the proteins that mediate the effects of RA. In contrast, the RAR alpha mRNA was detected in some but not all decidua/embryo complexes, both control and treated, suggesting that its expression is initiated at approxi mately GD 5, while RXR gamma mRNA was not detected. Examination of the cont rol and RA-exposed embryos on GD 10, 12, or 17 showed that greater than 50% of the RA-exposed embryos were adversely affected, many with defects found only after serial histopathological examination. The malformations were lo calized primarily in the central nervous system, the branchial arches, and their derivatives. These terata included excessive folding and elevation of the neural tube floor plate, exencephaly (with detachment of the cephalic neuroepithelium and rarefied cephalic mesenchyme), persistent patency of Ra thke's pouch, small trigeminal ganglia, neural diverticula (chiefly from th e spinal cord), and/or various optic and otic defects. Unexpectedly, limb r eduplications were not apparent in RA-exposed fetuses. Those litters examin ed on GD 17 had a high percentage of resorbed or malformed implantations, a nd the few apparently normal fetuses were developmentally delayed with repe ct to bone ossification. These data confirm that the development of neural- and neural crest-derived structures are severely disrupted by RA exposure prior to initial specification of the neural plate and suggest that many of the proteins that regulate RA signaling are available in early vertebrate embryos at this developmental stage.