LIMB AND LOWER-BODY DUPLICATIONS INDUCED BY RETINOIC ACID IN MICE

The zygote and subsequent preimplantation stages of early mammalian de velopment are susceptible to certain chemical perturbations that cause abnormal development of the conceptus. In certain cases, disruption i n patterns of gene expression could be a primary event leading to abno rmal development. To investigate this hypothesis, we treated pregnant mice with hans-retinoic acid, a known modulator of gene expression. Tr eatments were administered at various times during pregastrulation sta ges and the presumed onset of gastrulation. trans-Retinoic acid induce d a distinctive set of malformations, as manifest by supernumerary and ectopic limbs and duplication of portions of the lower body, but only when administered during the period of 4.5-5.5 days after mating. (Ot her malformations were induced at different stages.) The limb and lowe r-body duplications suggest that exogenous trans-retinoic acid may inf luence not only the pattern for the hindlimbs but also that for the en tire lower body. Since it appears likely that the embryos were affecte d in the late blastocyst and proamniotic-embryo stages, the provocativ e possibility arises that aspects of pattern formation of limbs and lo wer body actually occur prior to gastrulation.