Biological and biochemical consequences of global deletion of exon 3 from the ERα gene

To address issues resulting from alpha estrogen receptor-knockout (alpha ERKO) residual N-terminal truncated estrogen receptor alpha, and to allow tissue-selective deletion of ER alpha, we generated loxP-flanked exon 3 mice. Initial characterization of global sox2 cre-derived exon 3-deleted Ex3 alpha ERKO mice indicated no ER alpha protein in uterine tissue and recapitulation of previously described female phenotypes, confirming successful ablation of ER alpha. Body weights of Ex3 alpha ERKO female mice were 1.4-fold higher than wild-tupe (WT) females and comparable to WT males. Microarray indicated the Ex3 alpha ERKO uterus is free of residual estrogen responses. RT-PCR showed Nr4a1 is increased 41-fold by estrogen in WT and 7.4-fold in alpha ERKO, and not increased in Ex3 alpha ERKO. Nr4a1, Cdkn1a, and c-fos transcripts were evaluated in WT and Ex3 alpha ERKO mice following estrogen, IGF1, or EGF injections. All 3 were increased by all treatments in WT. None were increased by estrogen in Ex3 alpha ERKO. Nr4a1 increased 24.5- and 14.7-fold, Cdkn1a increased 14.2- and 12.3-fold, and c-fos increased 20.9-fold and 16.2-fold after IGF1 and EGF treatments, respectively, in the Ex3 alpha ERKO mice, confirming that growth factor regulation is independent of ER alpha. Our Ex3 alpha ER alpha model will be useful in studies of complete or selective ablation of ER alpha in target tissues.-Hewitt, S. C., Kissling, G. E., Fieselman, K. E., Jayes, F. L., Gerrish, K. E., Korach, K. S. Biological and biochemical consequences of global deletion of exon 3 from the ER alpha gene. FASEB J. 24, 4660-4667 (2010). www.fasebj.org