Human Molecular Genetics Advance Access published online on May 7, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp215
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Functional interaction of DYX1C1 with estrogen receptors suggests involvement of hormonal pathways in dyslexia
1 Department of Medical Genetics, University of Helsinki, and Folkhälsan Institute of Genetics, Helsinki, Finland 2 Department of Biosciences and Nutrition, Karolinska Institutet, and Clinical Research Centre, Karolinska University Hospital, Huddinge, Sweden 3 Neuroscience Centre, University of Helsinki, Finland 4 Department of Genetics and Pathology, Rudbeck Laboratory, University of Uppsala, Uppsala, Sweden 5 Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA
* To whom correspondence should be addressed at: Karolinska Institutet, Department of Biosciences and Nutrition, 14157 Huddinge, Sweden. Tel: +4686089158; Fax: +46 87745538; Email: juha.kere{at}biosci.ki.se; juha.kere{at}helsinki.fi
Received February 23, 2009; Revised May 2, 2009; Accepted May 2, 2009
Dyslexia, or specific reading disability, is the unexpected failure in learning to read and write when intelligence and senses are normal. One of the susceptibility genes, DYX1C1, has been implicated in neuronal migration, but little is known about its interactions and functions. As DYX1C1 was suggested to interact with the U-box protein CHIP (Carboxy terminus of Hsc70-Interacting Protein), which also participate in the degradation of estrogen receptors alpha (ER
) and beta (ERβ), we hypothesized that the effects of DYX1C1 might be at least in part mediated through regulation of estrogen receptors. ERs have shown to be important in brain development and cognitive functions. Indeed, we show that DYX1C1 interacts with both ERs in the presence of 17β-estradiol, as determined by co-localization, co-immunoprecipitation and proximity ligation assays. Protein levels of endogenous ER or exogenous ERβ were reduced upon over-expression of DYX1C1, resulting in decreased transcriptional responses to 17β-estradiol. Furthermore, we detected in vivo complexes of DYX1C1 with ER or ERβat endogenous levels along neurites of primary rat hippocampal neurons. Taken together, our data suggest that DYX1C1 is involved in the regulation of ER and ERβ, and may thus affect the brain development and regulate cognitive functions. These findings provide novel insights into the function of DYX1C1 and link neuronal migration and developmental dyslexia to the estrogen signaling effects in the brain.
Authors contributed equally