These results further demonstrate the ability of retinoids to influence embryonic development. EC19 and ATRA are effective at similar concentrations. In contrast, EC19, which is structurally very similar to EC23, has novel, less severe effects on the face and rarely alters limb development. EC23 also produces effects similar to those of ATRA on the developing face, producing reductions of the upper beak at concentrations two orders of magnitude lower than ATRA. This includes suppression of expression of the scapula marker Pax1. EC23 and ATRA are shown to have effects on the entire proximal–distal axis of the limb, including hitherto undescribed effects on the scapula. With EC23 application we also find digit 1 phenotypes similar to thumb duplications described in the clinical literature. This corresponds to differential effects of ATRA and EC23 on sonic hedgehog (shh) expression in the developing limb bud. When larger quantities of EC23 are applied, a novel phenotype is obtained involving production of multiple digit 1s on the anterior limb. We found that retinoid EC23 produces effects on the wing digits similar to ATRA, but does so at two orders of magnitude lower concentration. Retinoids were applied to the anterior limb buds of chicken embryos in ovo via ion-exchange beads. We present herein the first description of the effects of these molecules in vivo. Their effects on the differentiation of pluripotent stem cells has been previously described in vitro and are consistent with this hypothesis. Based on the position of the terminal carboxylic acid groups in the compounds we suggest that EC23 is a structural analogue of all-trans retinoic acid (ATRA), and EC19 is an analogue of 13-cis retinoic acid. They are stable on exposure to light and are predicted to be resistant to the normal metabolic processes involved in the inactivation of retinoids in vivo. We have recently developed a range of synthetic retinoid analogues which include the compounds EC23 and EC19.
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