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GSE30767
Mus musculus
1 Downloadable Sample
Description
This work was designed to determine the role of the vascular endothelial growth factor A (VEGF) isoforms during early neuroepithelial development in the mammalian central nervous system (CNS), specifically in the forebrain. An emerging model of interdependence between neural and vascular systems includes VEGF, with its dual roles as a potent angiogenesis factor and neural regulator. Although a number of studies have implicated VEGF in CNS development, little is known about the role that the different VEGF isoforms play in early neurogenesis. We used a mouse model of disrupted VEGF isoform expression that eliminates the predominant brain isoform, VEGF164, and expresses only the diffusible form, VEGF120. We tested the hypothesis that VEGF164 plays a key role in controlling neural precursor populations in developing cortex. We used microarray analysis to compare gene expression differences between wild type and VEGF120 mice at E9.5, the primitive stem cell stage of the neuroepithelium. We quantified changes in PHH3-positive nuclei, neural stem cell markers (Pax6 and nestin) and the Tbr2-positive intermediate progenitors at E11.5 when the neural precursor population is expanding rapidly. Absence of VEGF164 (and VEGF188) leads to reduced proliferation without an apparent effect on the number of Tbr2-positive cells. There is a corresponding reduction in the number of mitotic spindles that are oriented parallel to the ventricular surface relative to those with a vertical or oblique angle. These results support a role for the VEGF isoforms in supporting the neural precursor population of the early neuroepithelium.
Publication Title
Vascular endothelial growth factor (VEGF) isoform regulation of early forebrain development.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
Description
Cytosine methylation is an epigenetic mark usually associated with gene repression. Despite a requirement for de novo DNA methylation for differentiation of embryonic stem cells, its role in somatic stem cells is unknown. Using conditional ablation, we show that loss of either, or both, Dnmt3a or Dnmt3b, progressively impedes hematopoietic stem cell (HSC) differentiation during serial in vivo passage. Concomitantly, HSC self-renewal is immensely augmented in absence of either Dnmt3, particularly Dnmt3a. Dnmt3-KO HSCs show upregulation of HSC multipotency genes and downregulation of early differentiation factors, and the differentiated progeny of Dnmt3-KO HSCs exhibit hypomethylation and incomplete repression of HSC-specific genes. HSCs lacking Dnmt3a manifest hyper-methylation of CpG islands and hypo-methylation of genes which are highly correlated with human hematologic malignancies. These data establish that aberrant DNA methylation has direct pathologic consequences for somatic stem cell development, leading to inefficient differentiation and maintenance of a self-renewal program.
Publication Title
Dnmt3a is essential for hematopoietic stem cell differentiation.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
Description
Background & Aims: HNF4 is an important transcriptional regulator of hepatocyte and pancreatic function. Hnf4 deletion is embryonically lethal with severe defects in visceral endoderm formation, liver maturation and colon development. However, the precise role of this transcription factor in maintaining homeostasis of the adult intestine remains unclear. Herein, we aimed to elucidate the adult intestinal functions of Hnf4. Methods: A conditional intestinal epithelial Hnf4 knockout mouse was generated. Histological abnormality of the colonic mucosa was assessed by immunodetection and Western. Changes in global gene expression and biological network were analyzed. Results: Hnf4 intestine null mice developed normally until reaching young adulthood. Crypt distortion became apparent in the Hnf4 null colon at 3 months of age followed by focal areas of crypt dropout, increased immune cell infiltrates, crypt hyperplasia and early signs of polyposis later in life. A gene profiling analysis identified cell death and cell cycle related to cancer as the most significant sets of genes altered in the Hnf4 colon null mice. Expression levels of the tight junction proteins claudin 4, 8 and 15 were altered early in the colon epithelium of Hnf4 mutants and correlated with increased barrier permeability to a molecular tracer that does not normally penetrate normal mucosa. Conclusion: These observations support a functional role for Hnf4 in protecting the colonic mucosa against the initiation of the changes resembling inflammatory bowel diseases and polyp formation.
Publication Title
Loss of hepatocyte-nuclear-factor-4alpha affects colonic ion transport and causes chronic inflammation resembling inflammatory bowel disease in mice.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 26 Downloadable Samples
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 24 Downloadable Samples
Description
The Fragile X Mental Retardation Protein, FMRP, is thought to regulate the translation of a specific set of neuronal mRNAs on polyribosomes. Therefore, we prepared polyribosomes on sucrose gradients and purified mRNA specifically from these fractions, as well as the total mRNA levels, to determine whether a set of mRNAs might be changed in its % association with polyribosomes in the absence of FMRP in the KO mouse model.
Publication Title
FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 8 Downloadable Samples
Description
Normal erythropoiesis requires a critical balance between proapoptotic and antipaoptotic pathways. Bcl-xl, an antiapoptotic protein is induced at end-stages of differentiation of erythroid precursors in response to erythropoietin. The details of the proapoptotic pathway and the critical proapoptotic proteins inhibited by Bcl-xl in erythropoiesis are not well understood. We employed gene targeting to ablate Nix, a proapoptotic BH3-domain only Bcl2 family protein, which is known to be transcriptionally induced during erythropoiesis. Nix null mice exhibited reticulocytosis and thrombocytosis in the peripheral blood; and profound splenomegaly with erythroblastosis in the spleen and bone marrow despite normal erythropoietin levels and blood oxygen tension. In vivo apoptosis was diminished in erythroblast precursors from Nix null spleens. To define the molecular consequences of Nix ablation on apoptosis and erythropoiesis, we conducted a detailed comparative analysis of gene expression in spleens from 8 week old Nix null mice and wild type controls. Of 45,101 genes analyzed, 514 were significantly upregulated and 386 down-regulated in Nix-/- splenocytes. Functional cluster analysis delineated the ten most highly regulated gene sets, revealing increased levels of cell cycle and erythroid genes, with decreased levels of cell death and B-cell genes.
Publication Title
Unrestrained erythroblast development in Nix-/- mice reveals a mechanism for apoptotic modulation of erythropoiesis.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 4 Downloadable Samples
Description
Endothelial inflammation contributes to the pathogenesis of numerous human diseases; however, the role of tumor endothelial inflammation in the growth of experimental tumors and its influence on the prognosis of human cancers is less understood. TNF-, an important mediator of tumor stromal inflammation, is known to target the tumor vasculature. In this study, we demonstrate that B16-F1 melanomas grew more rapidly in C57BL/6 wild-type (WT) mice than in syngeneic mice with germline deletions of both TNF- receptors (KO). This enhanced tumor growth was associated with increased COX2 inflammatory expression in WT tumor endothelium compared to endothelium in KO mice. We purified endothelial cells from WT and KO tumors and characterized dysregulated gene expression, which ultimately formed the basis of a 6-gene Inflammation-Related Endothelial-derived Gene (IREG) signature. This inflammatory signature expressed in WT tumor endothelial cells was trained in human cancer datasets and predicted a poor clinical outcome in breast cancer, colon cancer, lung cancer and glioma. Consistent with this observation, conditioned media from human endothelial cells treated with pro-inflammatory cytokines (TNF- and interferons) accelerated the growth of human colon and breast tumors in immune-deprived mice as compared with conditioned media from untreated endothelial cells. These findings demonstrate that activation of endothelial inflammatory pathways contributes to tumor growth and progression in diverse human cancers.
Publication Title
Tumor endothelial inflammation predicts clinical outcome in diverse human cancers.
Sample Metadata Fields
Specimen part
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