Transcriptional interaction of an estrogen receptor splice variant and ErbB4 suggests convergence in gene susceptibility pathways in schizophrenia

Mounting evidence from clinical and basic research suggests that estrogen signaling may be altered in the brains of people with schizophrenia. Previously, we found that DNA sequence variation in the estrogen receptor (ER) α gene, lower ERα mRNA levels, and/or blunted ERα signaling is associated with schizophrenia. In this study, we asked whether the naturally occurring truncated ERα isoform, Δ7, which acts as a dominant negative, can attenuate gene expression induced by the wildtype (WT) receptor in an estrogen-dependent manner in neuronal (SHSY5Y) and non-neuronal (CHOK1 and HeLa) cells. In addition, we determined the extent to which ERα interacts with NRG1-ErbB4, a leading schizophrenia susceptibility pathway. Reductions in the transcriptionally active form of ErbB4 comprising the intracytoplasmic domain (ErbB4-ICD) have been found in schizophrenia, and we hypothesized that ERα and ErbB4 may converge to control gene expression. In the present study, we show that truncated Δ7-ERα attenuates WT-ERα-driven gene expression across a wide range of estrogen concentrations in cells that express functional ERα at base line or upon co-transfection of full-length ERα. Furthermore, we find that ErbB4-ICD can potentiate the transcriptional activity of WTERα at EREs in two cell lines and that this potentiation effect is abolished by the presence of Δ7-ERα. Immunofluorescence microscopy revealed nuclear co-localization of WT-ERα, Δ7-ERα, and ErbB4-ICD, whereas immunoprecipitation assays showed direct interaction. Our findings demonstrate convergence between ERα and ErbB4-ICD in the transcriptional control of ERα-target gene expression and suggest that this may represent a convergent pathway that may be disrupted in schizophrenia. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.