TY - JOUR
T1 - Functional interaction of DYX1C1 with estrogen receptors suggests involvement of hormonal pathways in dyslexia
AU - Massinen, Satu
AU - Tammimies, Kristiina
AU - Tapia-Páez, Isabel
AU - Matsson, Hans
AU - Hokkanen, Marie Estelle
AU - Söderberg, Ola
AU - Landegren, Ulf
AU - Castrén, Eero
AU - Gustafsson, Jan Åke
AU - Treuter, Eckardt
AU - Kere, Juha
N1 - Funding Information:
The study has been supported by Swedish Research Council, Swedish Royal Bank Tercentennial Foundation, Swedish Brain Foundation (Hjärnfonden), Knut and Alice Wallenberg Foundation, Swedish Cancer Foundation, Sigrid Jusélius Foundation, Päivikki and Sakari Sohlberg Foundation, Osk. Huttunen Foundation, Academy of Finland and European Union (Enlight and CRESCENDO).
PY - 2009
Y1 - 2009
N2 - 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 participates in the degradation of estrogen receptors alpha (ERα) and beta (ERβ), we hypothesized that the effects of DYX1C1 might be at least in part mediated through the regulation of ERs. 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 ERα 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 ERα or ERβ at endogenous levels along neurites of primary rat hippocampal neurons. Taken together, our data suggest that DYX1C1 is involved in the regulation of ERα 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.
AB - 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 participates in the degradation of estrogen receptors alpha (ERα) and beta (ERβ), we hypothesized that the effects of DYX1C1 might be at least in part mediated through the regulation of ERs. 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 ERα 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 ERα or ERβ at endogenous levels along neurites of primary rat hippocampal neurons. Taken together, our data suggest that DYX1C1 is involved in the regulation of ERα 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.
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U2 - 10.1093/hmg/ddp215
DO - 10.1093/hmg/ddp215
M3 - Article
C2 - 19423554
AN - SCOPUS:67650763685
SN - 0964-6906
VL - 18
SP - 2802
EP - 2812
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 15
ER -