Tamoxifen modulates apoptosis in multiple modes of action in CreER mice

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. genesis 46:775–781, 2008. © 2008 Wiley‐Liss, Inc.