Massinen Satu, Tammimies Kristiina, Tapia-Páez Isabel, Matsson Hans, Hokkanen Marie-Estelle, Söderberg Ola, Landegren Ulf, Castrén Eero, Gustafsson Jan-Ake, Treuter Eckardt, Kere Juha
Department of Medical Genetics, University of Helsinki and Folkhälsan Institute of Genetics, Helsinki, Finland.
Hum Mol Genet. 2009 Aug 1;18(15):2802-12. doi: 10.1093/hmg/ddp215. Epub 2009 May 7.
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 (ERalpha) and beta (ERbeta), 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 17beta-estradiol, as determined by co-localization, co-immunoprecipitation and proximity ligation assays. Protein levels of endogenous ERalpha or exogenous ERbeta were reduced upon over-expression of DYX1C1, resulting in decreased transcriptional responses to 17beta-estradiol. Furthermore, we detected in vivo complexes of DYX1C1 with ERalpha or ERbeta at endogenous levels along neurites of primary rat hippocampal neurons. Taken together, our data suggest that DYX1C1 is involved in the regulation of ERalpha and ERbeta, 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.
阅读障碍，即特定阅读障碍，是指在智力和感官正常的情况下，学习读写意外失败的情况。其中一个易感基因DYX1C1与神经元迁移有关，但其相互作用和功能却鲜为人知。由于有人提出DYX1C1与U-box蛋白CHIP（Hsc70相互作用蛋白的羧基末端）相互作用，而CHIP也参与雌激素受体α（ERα）和β（ERβ）的降解，我们推测DYX1C1的作用可能至少部分是通过对雌激素受体的调节来介导的。雌激素受体已被证明在大脑发育和认知功能中很重要。事实上，我们通过共定位、共免疫沉淀和邻近连接分析确定，在17β-雌二醇存在的情况下，DYX1C1与两种雌激素受体都相互作用。DYX1C1过表达后，内源性ERα或外源性ERβ的蛋白水平降低，导致对17β-雌二醇的转录反应减少。此外，我们在原代大鼠海马神经元神经突的内源性水平上检测到DYX1C1与ERα或ERβ的体内复合物。综上所述，我们的数据表明DYX1C1参与了ERα和ERβ的调节，因此可能影响大脑发育并调节认知功能。这些发现为DYX1C1的功能提供了新的见解，并将神经元迁移和发育性阅读障碍与大脑中的雌激素信号效应联系起来。
