Limb development in mouse embryos. I. Analysis of teratogenic effects of retinoic acid

Abstract

Retinoic (vitamin A) acid produced phocomelia and micromelia in DBA/2J fetuses when administered to pregnant mice on the 12th or 13th day of gestation. The incidence of forelimb defects was higher after 12th‐ (in embryos having 33–41 somite pairs) than 13th–day treatment (40–51 somite pairs); the reverse was true for hindlimb defects. Hindlimb digits continued to be highly susceptible on the 14th day. Limb defects were not accompanied by body growth retardation or other skeletal malformations except cleft palate. The type and severity of limb defects depended on the average developmental stage of the limb bud at the time of treatment. From the beginning of the period of limb susceptibility, the 12th day, the ontogenetic sequence in which the long bones were rendered abnormal was: radius–ulna, humerus, fibula, tibia, femur or tibia‐femur. The sequence in which the long bones lost their susceptibility to retinoic acid was: humerus, femur, ulna, radius, tibia‐fibula. The radius appeared to be susceptible in some embryos at a time when the other long bones had escaped injury. An analysis of the shape of the same bone affected at different periods of prenatal development led to the following proposal. At earlier stages retinoic acid disrupts cellular activities that normally lead to the spatial organization of the mesenchymal cell condensations, resulting in a modified shape of the cartilage models; at later stages it prevents the enlargement of the condensations that have already appeared, resulting in smaller than normal models.