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The miR-126/VEGFR2 axis controls the innate response to pathogen-associated nucleic acids

ABSTRACT: microRNA-126 is a microRNA predominately expressed by endothelial cells and controls angiogenesis. Unexpectedly, we found that mice deficient in miR-126 have a major impairment in their innate response to pathogen-associated nucleic acids, as well as HIV, which results in more widespread cell infection. Further examination revealed that this was due to miR-126 control of plasmacytoid DC (pDC) homeostasis and function, and that miR-126 regulates expression of TLR7, TLR9, NFkB1 and other innate response genes, as well as VEGF-receptor 2 (VEGFR2). Deletion of VEGFR2 on DCs resulted in reduced interferon production, supporting a role for VEGFR2 in miR-126 regulation of pDCs. These studies identify the miR-126/VEGFR2 axis as an important regulator of the innate response that operates through multiscale control of pDCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE51255 | GEO | 2013/11/24

SECONDARY ACCESSION(S): PRJNA222226

REPOSITORIES: GEO

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The miR-126/VEGFR2 axis controls the innate response to pathogen-associated nucleic acids

Project description:microRNA-126 is a microRNA predominately expressed by endothelial cells and controls angiogenesis. Unexpectedly, we found that mice deficient in miR-126 have a major impairment in their innate response to pathogen-associated nucleic acids, as well as HIV, which results in more widespread cell infection. Further examination revealed that this was due to miR-126 control of plasmacytoid DC (pDC) homeostasis and function, and that miR-126 regulates expression of TLR7, TLR9, NFkB1 and other innate response genes, as well as VEGF-receptor 2 (VEGFR2). Deletion of VEGFR2 on DCs resulted in reduced interferon production, supporting a role for VEGFR2 in miR-126 regulation of pDCs. These studies identify the miR-126/VEGFR2 axis as an important regulator of the innate response that operates through multiscale control of pDCs. Plasmactyoid dendritic cells were FACS-sorted from spleens from wildtype and miR-126 KO mice and their RNA extracted. RNA was amplified, labeled and hybridized to Mouse Gene 1.0 ST arrays with the data generation and quality control pipeline of 19 the Immunological Genome Project (www.immgen.org). Raw data were background-corrected and normalized using the RMA algorithm.

2013-11-24 | E-GEOD-51255 | biostudies-arrayexpress

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Project description:"The analysis was designed to search for putative seed sequences for miR-126 in the 3’UTR of up-regulated genes. ECs were co-transfected with anti-miR-126 and a plasmid vector bearing the GFP-coding sequence and three complementary sites for miR-126 downstream. As a consequence of the presence of miR-126 binding sites the GFP expression was under the control of miR-126. Fluorescente cells were the cells transfected with anti-miR-126 oligo. MiR-126 target enrichment analysis was performed on the basis of the Miranda database, as provided by Diana miRGen. Significance was estimated on the basis of hyper geometric distribution p-values comparing the occurrence of miR targets in the signature with respect to the universe, defined as the genes expressed in HUVEC. Frequency of log 2 ratio between the subset of mir-126 targets and the genes which are not targets of miR-126 were plotted, highlighting enrichment of the target of miR in differentially regulated genes. "

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E-GEOD-51255

Project description:The miR-126/VEGFR2 axis controls the innate response to pathogen-associated nucleic acids

2015-07-27 | E-GEOD-51255 | ExpressionAtlas

miR-126 Orchestrates an Oncogenic Program in B-Cell Precursor Acute Lymphoblastic Leukemia

Project description:MicroRNA (miRNA)-126 is a known regulator of hematopoietic stem cell quiescence. We engineered murine hematopoiesis to express miRNA-126 across all differentiation stages. Thirty percent of mice developed monoclonal B cell leukemia, which was prevented or regressed when a tetracycline-repressible miRNA-126 cassette was switched off. Regression was accompanied by upregulation of cell-cycle regulators and B cell differentiation genes, and downregulation of oncogenic signaling pathways. Expression of dominant-negative p53 delayed blast clearance upon miRNA-126 switch-off, highlighting the relevance of p53 inhibition in miRNA-126 addiction. Forced miRNA-126 expression in mouse and human progenitors reduced p53 transcriptional activity through regulation of multiple p53-related targets. miRNA-126 is highly expressed in a subset of human B-ALL, and antagonizing miRNA-126 in ALL xenograft models triggered apoptosis and reduced disease burden. Study 1: Turning off miR-126 expression from an experimental murine B-ALL in vivo; Study 2: Modulation of miR-126 expression in human cord blood stem and progenitor cell populations in vitro.

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