Unr (upstream of N-ras) is a cytoplasmic RNA-binding protein with cold shock domains, involved in regulation of messenger RNA stability and translation. To address the biological role of Unr, we inactivated the unr gene by homologous recombination in mice and embryonic stem (ES) cells. Embryos deficient for Unr die at mid-gestation, and the main phenotypic defects observed, growth deficiency and absence of neural tube closure, suggest a role of Unr in the balance proliferation/differentiation during early development. Here, we report that in Unr-null ES cell cultures, we observed a greater proportion of partially differentiated colonies, together with dispersed, refractile cells with stellate morphology, reminiscent of primitive endoderm (PrE) cells. DNA microarray, immunostaining, and RNA analyses revealed that Unr-null ES cells express a set of PrE markers, including the GATA6 transcription factor, a key inducer of PrE. Although Unr-deficient cells did not downregulate the pluripotency regulators Oct4, Nanog and Sox2, they grew more slowly than the wild-type lines, and their clonogenicity was lower. Silencing of Unr by RNA interference in ES E14 (129 genetic background) resulted in similar phenotypic and molecular changes as those observed in unr-/- ES cells (C57Bl/6 background). Finally, we show that ectopic expression of Unr in unr-/- ES cells partially reverses the endoderm-specific gene expression and the differentiation phenotype.
The RNA-binding protein Unr prevents mouse embryonic stem cells differentiation toward the primitive endoderm lineage.
Specimen part, Treatment
View SamplesMedulloblastoma is the most common pediatric CNS cancer. In order to identify important molecules important for deregulated tumor cell growth, we use microarray to detail the global gene expression profile in Shh-driven mouse medulloblastomas and determine the most differentially expressed genes compared to the control wild-type cerebellum.
Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics.
Age, Specimen part
View SamplesZBTB4 is a mammalian transcription factor with Zinc fingers and a BTB/POZ domain, which can bind methylated CpGs, as well as certain unmethylated consensus sequences. ZBTB4 is frequently downregulated in human cancers, but it is unclear whether this is a cause or consequence of transformation. To investigate the role of ZBTB4 in normal and pathological conditions, we generated Zbtb4-/- mice
Loss of the Methyl-CpG-Binding Protein ZBTB4 Alters Mitotic Checkpoint, Increases Aneuploidy, and Promotes Tumorigenesis.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Norrin/Frizzled4 signalling in the preneoplastic niche blocks medulloblastoma initiation.
Specimen part
View SamplesMedulloblastoma (MB), a tumor of the cerebellum, is the most common malignant brain tumor in children. One third of all human MB exhibits a gene expression signature of Sonic hedgehog (Shh) signaling. Hedgehog (Hh) pathway inhibitors have shown efficacy in clinical trials for MB, however, tumors develop resistance to these compounds, highlighting the need to identify additional therapeutic targets for treatment. We have identified a role for Norrin signaling in tumor initiation in the Patched (Ptch) mouse model of MB. Norrin is a secreted factor that functions as an atypical Wnt by binding to the Frizzled4 (Fzd4) receptor on endothelial cells to activate canonical beta-catenin-mediated Wnt signaling pathway. In the cerebellum, activation of Norrin/Fzd4 signaling is required for the establishment and maintenance of the blood brain barrier (BBB). We have identified a role for Norrin signaling in the stroma as a potent tumor inhibitory signal. Inactivation of Norrin in Ptch+/- mice significantly shortens latency and increases MB incidence. This phenotype is associated with an increased frequency of pre-tumor lesions and their conversion to malignancy. In this context, loss of Norrin signalling in endothelial cells is associated with an accelerated transition to a pro-tumor stroma characterized by vascular permeability, inflammation and angiogenic remodelling. Accordingly, loss of Ndp significantly alters the stromal gene expression signature of established Ptch MB.
Norrin/Frizzled4 signalling in the preneoplastic niche blocks medulloblastoma initiation.
Specimen part
View SamplesMedulloblastoma (MB), a tumor of the cerebellum, is the most common malignant brain tumor in children. One third of all human MB exhibits a gene expression signature of Sonic hedgehog (Shh) signaling. Hedgehog (Hh) pathway inhibitors have shown efficacy in clinical trials for MB, however, tumors develop resistance to these compounds, highlighting the need to identify additional therapeutic targets for treatment. We have identified a role for Norrin signaling in tumor initiation in the Patched (Ptch) mouse model of MB. Norrin is a secreted factor that functions as an atypical Wnt by binding to the Frizzled4 (Fzd4) receptor on endothelial cells to activate canonical beta-catenin-mediated Wnt signaling pathway. In the cerebellum, activation of Norrin/Fzd4 signaling is required for the establishment and maintenance of the blood brain barrier (BBB). We have identified a role for Norrin signaling in the stroma as a potent tumor inhibitory signal. Inactivation of Norrin in Ptch+/- mice significantly shortens latency and increases MB incidence. This phenotype is associated with an increased frequency of pre-tumor lesions and their conversion to malignancy. In this context, loss of Norrin signalling in endothelial cells is associated with an accelerated transition to a pro-tumor stroma characterized by vascular permeability, inflammation and angiogenic remodelling. Accordingly, loss of Ndp significantly alters the stromal gene expression signature of established Ptch MB.
Norrin/Frizzled4 signalling in the preneoplastic niche blocks medulloblastoma initiation.
Specimen part
View SamplesTranscript data from livers from fasted-state BXD strains on chow or high fat diet
Multilayered genetic and omics dissection of mitochondrial activity in a mouse reference population.
Specimen part
View SamplesCharacterizing the impact of pharmacological and shRNA-mediated silencing of EAG2 in medulloblastoma.
EAG2 potassium channel with evolutionarily conserved function as a brain tumor target.
Specimen part, Cell line
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Medulloblastoma subgroups remain stable across primary and metastatic compartments.
Sex, Age, Specimen part, Subject
View SamplesAffymetrix Human Gene 2.0 ST Array profiling of 9 pairs of matched primary-metastases medulloblastoma samples.
Medulloblastoma subgroups remain stable across primary and metastatic compartments.
Sex, Age, Specimen part, Subject
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