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Tamoxifen modulates apoptosis in multiple modes of action in CreER mice
Abstract:
Tamoxifen-inducible Cre (CreER) has become a powerful tool for in vivo manipulation of the genome. Here, we investigated opposing effects of tamoxifen on apoptosis during embryogenesis using Olig2-CreER knock-in mice, namely, tamoxifen-induced apoptosis through CreER-mediated toxicity and cytoprotective activity of tamoxifen independent of CreER. First, we examined tamoxifen-induced apoptosis; in the homozygous mice, we observed region-specific apoptosis in the ventral neural tube, with no obvious increase in the heterozygotes. Next, we detected a cytoprotective effect on apoptosis in the homozygous dorsal root ganglia (DRG). This apoptosis is a secondary phenotype of Olig2-null mice, as Olig2/CreER is not expressed in the DRG. The cytoprotective effect is DRG-specific, because tamoxifen did not rescue apoptosis in the interdigital mesenchyme. These data indicate that tamoxifen has multiple effects on apoptosis during development and caution that careful examination is necessary when interpreting results obtained from tamoxifen-induced recombination: in Olig2-CreER mice, heterozygotes are usable for lineage-tracing experiment without obvious toxicity, while homozygotes show efficient recombination, despite enhanced apoptosis.
Insights
Tamoxifen has dual effects on embryonic apoptosis. Olig2-CreER mice show tamoxifen-induced toxicity in the neural tube but cytoprotection in dorsal root ganglia, impacting genome manipulation studies.
Area of Science:
- Developmental Biology
- Genetics
- Molecular Biology
Background:
- Tamoxifen-inducible Cre (CreER) systems are vital for in vivo genetic manipulation.
- Investigating the complex roles of tamoxifen in embryonic development is crucial for understanding CreER system applications.
Discussion:
- Tamoxifen exhibits opposing effects on apoptosis during embryogenesis in Olig2-CreER mice.
- CreER-mediated toxicity induces region-specific apoptosis in the ventral neural tube of homozygous mice.
- Tamoxifen independently confers a cytoprotective effect on apoptosis in dorsal root ganglia (DRG).
Key Insights:
- The cytoprotective effect in DRG is specific and not a direct result of Olig2/CreER expression.
- Tamoxifen's dual actions necessitate careful interpretation of results from tamoxifen-induced recombination experiments.
- Olig2-CreER heterozygotes are suitable for lineage tracing with minimal toxicity, while homozygotes exhibit efficient recombination but increased apoptosis.
Outlook:
- Further research is needed to elucidate the precise mechanisms behind tamoxifen's dual apoptotic effects.
- Optimizing tamoxifen dosage and timing is essential for reliable genetic manipulation using CreER systems.
- These findings have implications for designing safer and more effective gene-editing strategies in developmental studies.
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