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Limb and lower-body duplications induced by retinoic acid in mice
J C Rutledge1, A G Shourbaji, L A Hughes
1Department of Laboratory Medicine, Children's Hospital, Seattle, WA.
Abstract:
The zygote and subsequent preimplantation stages of early mammalian development are susceptible to certain chemical perturbations that cause abnormal development of the conceptus. In certain cases, disruption in patterns of gene expression could be a primary event leading to abnormal development. To investigate this hypothesis, we treated pregnant mice with trans-retinoic acid, a known modulator of gene expression. Treatments were administered at various times during pregastrulation stages and the presumed onset of gastrulation. trans-Retinoic acid induced 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. (Other malformations were induced at different stages.) The limb and lower-body duplications suggest that exogenous trans-retinoic acid may influence not only the pattern for the hindlimbs but also that for the entire lower body. Since it appears likely that the embryos were affected in the late blastocyst and proamniotic-embryo stages, the provocative possibility arises that aspects of pattern formation of limbs and lower body actually occur prior to gastrulation.
Insights
Early mammalian development is sensitive to gene expression disruptions. Exposure to trans-retinoic acid during critical pre-gastrulation stages caused limb and lower body duplications in mouse embryos.
Area of Science:
- Developmental Biology
- Teratology
- Genetics
Background:
- Mammalian embryonic development is vulnerable to chemical insults.
- Gene expression pattern disruptions can lead to abnormal development.
- Retinoic acid is a known gene expression modulator.
Purpose of the Study:
- To investigate if trans-retinoic acid exposure during early development causes abnormal embryonic development.
- To determine the critical window for trans-retinoic acid-induced malformations.
Main Methods:
- Pregnant mice were treated with trans-retinoic acid at various stages before and during gastrulation.
- Malformations were assessed in the resulting conceptuses.
Main Results:
- Trans-retinoic acid administration between 4.5-5.5 days post-mating induced limb and lower body duplications.
- These malformations suggest a role for gene expression modulation in early pattern formation.
- The timing of exposure points to effects during late blastocyst and proamniotic-embryo stages.
Conclusions:
- Exogenous trans-retinoic acid can disrupt normal embryonic patterning.
- Pattern formation for limbs and the lower body may occur before gastrulation.
- Early developmental stages are critical for preventing chemical-induced teratogenesis.