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 3 3 4 1 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 i n 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 mesenchy-ma1 cell condensations, resulting in a modified shape of the cartilage models; at later stages i t prevents the enlargement of the condensations that have already appeared, resulting in smaller than normal models.

Pattern duplication by retinoic acid treatment in the regenerating limbs of Korean salamander larvae, Hynobius leechii, correlates well with the extent of dedifferentiation

“…In the mouse fetus, the types of limb defects are variable and dependent on the exposure time and the stage of limb development. Types of defects can be from longbone deficiencies to deficiencies of digits (Kochhar, 1973;Sulik and Dehart, 1988). In regenerating axolotl limbs, administration of RA either too soon, before cells are dedifferentiated, or too late, after cells have redifferentiated, results in little or no pattern duplication (Thorns and Stocum, 1984;Maden et al, 1985;Niazi et al, 1985;Scadding and Maden, 1986a).…”

“…However, in excess, retinoids act as potent teratogenic agents in many developing systems. For example, excess retinoic acid (RA) can lead to craniofacial abnormalities, limb reduction, and digit deletion in mouse embryos (Kochhar, 1973;. In the developing chick wingbuds and regenerating amphibian limbs, RA causes an alteration of skeletal pattern including duplication and hypomorphism (Maden, 1982;Tickle et al, 1982;Kim and Stocum, 1986a;Lee and Kim, 1990).…”

The role of retinoic acid in embryonic and post-embryonic development

“…defects in the CNS, eye, face, dentition, ear, limb, urogenital system, cardiovascular system and the vertebrae and ribs (Knudsen, 1966;Shenfelt, 1972;Kochhar, 1973;Fantel et al 1977;Lammer et al 1985;Rosa et al 1986). Thus, we may reasonably conclude that since either too much or too little RA is harmful to the embryo, embryonic cells must strictly regulate the levels of endogenous RA so that the correct balance is obtained.…”

Genetic Regulation of Embryological Limb Development with Relation to Congenital Limb Deformity in Humans

“…Both high and low levels of retinoic acid have been implicated in a wide range of developmental abnormalities [31,32], and control of concentrations of RA is finely controlled in vivo. Retinoic acid signalling is implicated in chrondroblast differentiation and chondrocyte hypertrophy [27].…”