Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of mouse wild type and Stat5a or 5b knock-out blood cells treated with GM-CSF to induce granulopoiesis

ABSTRACT: GM-CSF controls the development of granulocytes but little is known about the contribution of the downstream mediating transcription factor STAT5A/B. To elucidate this pathway, we generated mice lacking the Stat5a and 5b genes in blood cells. Peripheral neutrophils were decreased and administration of 5-FU and GM-CSF failed to induce granulopoiesis in Stat5a/b-mutant mice. GMPs were isolated and cultured with GM-CSF. Both the number and size of STAT5A/B-null colonies were reduced and GM-CSF-induced survival of mature STAT5A/B-null neutrophils was impaired. Time-lapse cinematography and single cell tracking of GMPs revealed that STAT5A/B-null cells were characterized by a longer generation time and an increased cell death. Gene expression profiling experiments suggested that STAT5A/B directs GM-CSF signaling through the regulation of cell survival genes. Experiment Overall Design: Mice lacking or with the Stat5a and 5b genes in blood cells, which were treated w/o GMP

ORGANISM(S): Mus musculus

SUBMITTER: WeiPing Chen

PROVIDER: E-GEOD-14672 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

The transcription factors STAT5A/B regulate GM-CSF-mediated granulopoiesis.

Kimura Akiko A Rieger Michael A MA Simone James M JM Chen Weiping W Wickre Mark C MC Zhu Bing-Mei BM Hoppe Philipp S PS O'Shea John J JJ Schroeder Timm T Hennighausen Lothar L

Blood 20090924 21

Neutrophils play a vital role in the immune defense, which is evident by the severity of neutropenia causing life-threatening infections. Granulocyte macrophage-colony stimulating factor (GM-CSF) controls homeostatic and emergency development of granulocytes. However, little is known about the contribution of the downstream mediating transcription factors signal transducer and activator of transcription 5A and 5B (STAT5A/B). To elucidate the function of this pathway, we generated mice with compl ...[more]

PMID: 19779039

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Project description:Iron is essential for all cells but is toxic in excess, so iron absorption and distribution are tightly regulated. Serum iron is bound to transferrin and primarily enters erythroid cells via receptor-mediated endocytosis of the transferrin receptor (Tfr1). Tfr1 is essential for developing erythrocytes and reduced Tfr1 expression is associated with anemia. The transcription factors STAT5A/B are activated by many cytokines, including erythropoietin. Stat5a/b-/- mice are severely anemic and die perinatally, but no link has been made to iron homeostasis. To study the function of STAT5A/B in vivo, we deleted the floxed Stat5a/b locus in hematopoietic cells with a Tie2-Cre transgene. These mice exhibited microcytic, hypochromic anemia, as did lethally irradiated mice transplanted with Stat5a/b-/- fetal liver cells. Flow cytometry and RNA analyses of erythroid cells from mutant mice revealed a 50% reduction in Tfr1 mRNA and protein. We detected STAT5A/B binding sites in the first intron of the Tfr1 gene and found that expression of constitutively active STAT5A in an erythroid cell line increased Tfr1 levels. Chromatin immunoprecipitation experiments confirmed the binding of STAT5A/B to these sites. We conclude that STAT5A/B is an important regulator of erythroid progenitor iron uptake via its control of Tfr1 transcription. Experiment Overall Design: Isolated Ter119-positive fetal liver cells from three to five E14.5 embryos of the same genotype were combined, and total RNA was extracted using TRIzol reagent (Life Technologies) with two additional ethanol precipitations. RNA quality was verified using an Agilent Bioanalyzer (Agilent Technologies). Microarray analyses were performed using Affymetrix Mouse Genome 430 2.0 array GeneChips (Affymetrix). Up- and down-regulated genes were selected based on P values of <0.05 and fold changes of >1.5 or -1.5 as assessed by ANOVA using Partek Pro software (Partek). To determine specific pathways, gene pathway analysis was obtained using the statistically significant gene list (P<0.05) represented on the chip.

Dataset Information

Transcription profiling of mouse wild type and Stat5a or 5b knock-out blood cells treated with GM-CSF to induce granulopoiesis

Publications

The transcription factors STAT5A/B regulate GM-CSF-mediated granulopoiesis.

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