DYX1C1 functions in neuronal migration in developing neocortex
ABSTRACT Rodent homologues of two candidate dyslexia susceptibility genes, Kiaa0319 and Dcdc2, have been shown to play roles in neuronal migration in developing cerebral neocortex. This functional role is consistent with the hypothesis that dyslexia susceptibility is increased by interference with normal neural development. In this study we report that in utero RNA interference against the rat homolog of another candidate dyslexia susceptibility gene, DYX1C1, disrupts neuronal migration in developing neocortex. The disruption of migration can be rescued by concurrent overexpression of DYX1C1, indicating that the impairment is not due to off-target effects. Transfection of C- and N-terminal truncations of DYX1C1 shows that the C-terminal TPR domains determine DYX1C1 intracellular localization to cytoplasm and nucleus. RNAi rescue experiments using truncated versions of DYX1C1 further indicate that the C-terminus of DYX1C1 is necessary and sufficient to DYX1C1’s function in migration. In conclusion, DYX1C1, similar to two other candidate dyslexia susceptibility genes, functions in neuronal migration in rat neocortex.
Article: The dyslexia-associated gene KIAA0319 encodes highly N- and O-glycosylated plasma membrane and secreted isoforms.[show abstract] [hide abstract]
ABSTRACT: The KIAA0319 gene has been recently associated with developmental dyslexia and shown to be involved in neuronal migration. The deduced KIAA0319 protein contains several polycystic kidney disease (PKD) domains which may mediate the interaction between neurons and glial fibres during neuronal migration. We have previously reported the presence of several alternative splicing variants, some of which are predicted to affect the deduced protein. In this study, we over-expressed constructs containing the main form (A) and two alternative variants (B and C) of KIAA0319. We show that the full-length KIAA0319 (A) is a type I plasma membrane protein, a topology consistent with its proposed function in neuronal migration. The oligomeric status of KIAA0319 is mainly dimeric, and this condition depends on the cysteine-rich regions of the protein, especially the transmembrane (TM) domain and surrounding sequence. KIAA0319 is highly glycosylated in different mammalian cell lines. The central region including the PKD domains is N-glycosylated. Furthermore, a short fragment N-terminal to the PKD domains contains mucin-type O-glycosylation. The two alternative isoforms are soluble proteins lacking the TM domain and, interestingly, only isoform B is secreted. KIAA0319-deletion proteins lacking the TM domain were also secreted. These results suggest that KIAA0319 could be involved not only in cell-cell interactions, but also in signalling.Human Molecular Genetics 04/2008; 17(6):859-71. · 7.64 Impact Factor
Article: The dyslexia candidate gene DYX1C1 is a potential marker of poor survival in breast cancer.[show abstract] [hide abstract]
ABSTRACT: The dyslexia candidate gene, DYX1C1, shown to regulate and interact with estrogen receptors and involved in the regulation of neuronal migration, has recently been proposed as a putative cancer biomarker. This study was undertaken to assess the prognostic value and therapy-predictive potential of DYX1C1 mRNA and protein expression in breast cancer. DYX1C1 mRNA expression was assessed at the mRNA level in three independent population-derived patient cohorts. An association to estrogen/progesterone receptor status, Elston grade, gene expression subtype and lymph node status was analyzed within these cohorts. DYX1C1 protein expression was examined using immunohistochemistry in cancer and normal breast tissue. The statistical analyses were performed using the non-parametric Wilcoxon rank-sum test, ANOVA, Fisher's exact test and a multivariate proportional hazard (Cox) model. DYX1C1 mRNA is significantly more highly expressed in tumors that have been classified as estrogen receptor α and progesterone receptor-positive. The expression of DYX1C1 among the molecular subtypes shows the lowest median expression within the basal type tumors, which are considered to have the worst prognosis. The expression of DYX1C1 is significantly lower in tumors graded as Elston grade 3 compared with grades 1 and 2. DYX1C1 protein is expressed in 88% of tumors and in all 10 normal breast tissues examined. Positive protein expression was significantly correlated to overall survival (Hazard ratio 3.44 [CI 1.84-6.42]) of the patients but not to any of the variables linked with mRNA expression. We show that the expression of DYX1C1 in breast cancer is associated with several clinicopathological parameters and that loss of DYX1C1 correlates with a more aggressive disease, in turn indicating that DYX1C1 is a potential prognostic biomarker in breast cancer.BMC Cancer 02/2012; 12:79. · 3.01 Impact Factor