A distinctive gene expression fingerprint in mentally retarded male patients reflects disease-causing defects in the histone demethylase KDM5C

Background: Mental retardation is a genetically heterogeneous disorder, as more than 90 genes for this disorder has been found on the X chromosome alone. In addition the majority of patients are non-syndromic in that they do not present with clinically recognisable features. This makes it difficult to determine the molecular cause of this disorder on the basis of the phenotype alone. Mutations in KDM5C (previously named SMCX or JARID1C), a gene that encodes a transcriptional regulator with histone demethylase activity specific for dimethylated and trimethylated H3K4, are a comparatively frequent cause of non-syndromic X-linked mental retardation (NS-XLMR). Specific transcriptional targets of KDM5C, however, are still unknown and the effects of KDM5C deficiency on gene expression have not yet been investigated. Results: By whole-mount in situ hybridisation we showed that the mouse homologue of KDM5C is expressed in multiple tissues during mouse development. We present the results of gene expression profiling performed on lymphoblastoid cell lines as well as blood from patients with mutations in KDM5C. Using whole genome expression arrays and quantitative reverse transcriptase polymerase chain reaction (QRT-PCR) experiments, we identified several genes, including CMKOR1, KDM5B and KIAA0469 that were consistently deregulated in both tissues. Conclusions: Our findings shed light on the pathological mechanisms underlying mental retardation and have implications for future diagnostics of this heterogeneous disorder

Cloning of mouse ojoplano, a reticular cytoplasmic protein expressed during embryonic development

6 páginas, 4 figuras, 1 tabla de sequencia de datos (NCBI accession number EU683438).Ojoplano (Opo) is a morphogenetic gene playing an important role during embryogenesis in medaka. This report focuses on the identification and characterization of the mouse Opo gene. We examined Opo expression by whole-mount in situ hybridization and in situ hybridization on sagittal sections during mouse embryogenesis. First expression in whole-mounts was detected at Theiler stages 15–17 (E 9.5–10.5 dpc) as a spotted specific staining in migrating neural crest cells and in placodal structures. A complex expression pattern was observed in Theiler stage 22–23 (E 14.5 dpc) in sagittal sections, including expression in skeletal structures (skull, vertebrae, ribs, bones of the locomotor system), in the nasal region, the heart and the eye. Fusion proteins revealed the localization of OPO within the cytoplasm with a reticular distribution that largely overlapped with the endoplasmic reticulum. Opo shows homology to human transcripts linked to a hereditary craniofacial malformation, orofacial cleft 1 (OFC1). The expression of mouse Opo in neural crest derivatives and skull elements further supports this link.This work was supported by the Max Planck Society.Peer reviewe

An RNA interference phenotypic screen identifies a role for FGF signals in colon cancer progression

In tumor cells, stepwise oncogenic deregulation of signaling cascades induces alterations of cellular morphology and promotes the acquisition of malignant traits. Here, we identified a set of 21 genes, including FGF9, as determinants of tumor cell morphology by an RNA interference phenotypic screen in SW480 colon cancer cells. Using a panel of small molecular inhibitors, we subsequently established phenotypic effects, downstream signaling cascades, and associated gene expression signatures of FGF receptor signals. We found that inhibition of FGF signals induces epithelial cell adhesion and loss of motility in colon cancer cells. These effects are mediated via the mitogen-activated protein kinase (MAPK) and Rho GTPase cascades. In agreement with these findings, inhibition of the MEK1/2 or JNK cascades, but not of the PI3K-AKT signaling axis also induced epithelial cell morphology. Finally, we found that expression of FGF9 was strong in a subset of advanced colon cancers, and overexpression negatively correlated with patients' survival. Our functional and expression analyses suggest that FGF receptor signals can contribute to colon cancer progression