Multiple structurally distinct ERα mRNA variants in zebrafish are differentially expressed by tissue type, stage of development and estrogen exposure
- Authors
- Cotter, K.A., Yershov, A., Novillo, A., and Callard, G.V.
- ID
- ZDB-PUB-131108-4
- Date
- 2013
- Source
- General and comparative endocrinology 194: 217-229 (Journal)
- Registered Authors
- Callard, Gloria V., Novillo, Apolonia
- Keywords
- Estrogen receptor alpha, mRNA variants, Zebrafish, Alternative splicing, Endocrine disruption
- MeSH Terms
-
- Alternative Splicing/genetics
- Animals
- Brain/drug effects
- Brain/metabolism
- Estrogen Receptor alpha/genetics*
- Estrogens/pharmacology
- Eye/drug effects
- Eye/metabolism
- Gene Expression/drug effects
- Gonads/drug effects
- Gonads/metabolism
- Liver/drug effects
- Liver/metabolism
- Myocardium/metabolism
- RNA, Messenger/genetics*
- Zebrafish/genetics*
- PubMed
- 24090614 Full text @ Gen. Comp. Endocrinol.
- CTD
- 24090614
It is well established that estrogen-like environmental chemicals interact with the ligand-binding site of estrogen receptors (ERs) to disrupt transcriptional control of estrogen responsive targets. Here we investigate the possibility that estrogens also impact splicing decisions on estrogen responsive genes, such as that encoding ERα itself. Targeted PCR cloning was applied to identify six ERα mRNA variants in zebrafish. Sequencing revealed alternate use of transcription and translation start sites, multiple exon deletions, intron retention and alternate polyadenylation. As determined by quantitative (q)PCR, N-terminal mRNA variants predicting long (ERαL) and short (ERαS) isoforms were differentially expressed by tissue-type, sex, stage of development and estrogen exposure. Whereas ERαL mRNA was diffusely distributed in liver, brain, heart, eye, and gonads, ERαS mRNA was preferentially expressed in liver (female > male) and ovary. Neither ERαL nor ERαS transcripts varied significantly during development, but 17β-estradiol selectively increased accumulation of ERαS mRNA (<170-fold by 120 hpf), an effect mimicked by bisphenol-A and diethylstilbestrol. Significantly, a C-truncated variant (ERαS-Cx) lacking most of the ligand binding and AF-2 domains was transcribed exclusively from the short isoform promoter and was similar to ERαS in its tissue-, stage- and estrogen inducible expression. These results support the idea that promoter choice and alternative splicing of the esr1 gene of zebrafish are part of the autoregulatory mechanism by which estrogen modulates subsequent ERα expression, and further suggest that environmental estrogens could exert some of their toxic effects by altering the relative abundance of structurally and functionally distinct ERα isoforms.