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.

No abstract

No abstract

Vitamin A and its analogs (retinoids) have acquired particular significance in embryonic development since the discovery that retinoic acid (RA) possesses properties of an endogenous morphogen and that embryonic tissues contain specific nuclear receptors for RA. Since the mammalian embryo does not synthesize RA de novo but rather must acquire it directly or in a precursor form from the maternal circulation, we sought to establish the relationship between levels of RA, retinol, and retinyl esters in the maternal system and their acquisition by the embryo, particularly during organogenesis in the mouse. Results indicate profound changes in maternal vitamin A levels during pregnancy in the mouse. These changes were characterized by a large, transient decrease in plasma retinol levels coincident with the period of organogenesis (e.g. gestational Days 9-14), and an apparent increase in mobilization from hepatic stores to the conceptus. During organogenesis, the embryo exhibited a steady increase in retinol levels with little increase in retinyl esters and virtually no change in RA. Analysis of retinoid accumulation patterns in the embryonic liver indicate that functional onset of vitamin A storage occurs by mid-organogenesis. In contrast, placental levels of these retinoids remained unchanged throughout organogenesis. Analysis of the conceptus as a developmental unit revealed that during early organogenesis the majority of retinoids are contained in the placenta (8-fold more than in the embryo). However, by mid-organogenesis the retinoid content of the embryo exceeds that of the placenta. Together, these results provide evidence that pregnancy in the mouse is accompanied by pronounced alterations in maternal retinoid homeostasis that occur coincident with the period of high embryonic sensitivity to exogenous retinoids.

Because both PBX and MEIS (and their orthologs) are believed to be involved in the control of proximodistal axis formation in mouse and fly limbs and IGFs in the development of limbs, we suggest that increases in PBX, MEIS and IGF-1 mRNA levels may contribute to proximodistal limb reduction defects caused by teratogenic doses of RA.