Unknown,Transcriptomics,Genomics,Proteomics

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Expression from hemocytes misexpressing Idh-R195H vs. controls

ABSTRACT: Expression profile for hemocytes from hml-Gal4, UAS-2xEGFP larvae were compared to hemocytes from hml-Gal4, UAS-2xEGFP; UAS-Idh-R195H larvae We sought to determine which genes and pathways were upregulated or downregulated in hemocytes expressing Idh-R195H, the Drosophila homolog of the human cancer-associated IDH1-R132H mutant, in vivo. We sought to obtain homogeneous populations of hemocytes from each genotype. We compared larvae expressing Idh-R195H from the hml-Gal4 driver to larvae with the hml-Gal4 driver alone.

ORGANISM(S): Drosophila melanogaster

SUBMITTER: Zachary Reitman

PROVIDER: E-GEOD-62008 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Genetic dissection of leukemia-associated IDH1 and IDH2 mutants and D-2-hydroxyglutarate in Drosophila.

Reitman Zachary J ZJ Sinenko Sergey A SA Spana Eric P EP Yan Hai H

Blood 20141114 2

Gain-of-function mutations in nicotinamide adenine dinucleotide phosphate-dependent isocitrate dehydrogenase (IDH)1 and IDH2 frequently arise in human leukemias and other cancers and produce high levels of D-2-hydroxyglutarate (D-2HG). We expressed the R195H mutant of Drosophila Idh (CG7176), which is equivalent to the human cancer-associated IDH1-R132H mutant, in fly tissues using the UAS-Gal4 binary expression system. Idh-R195H caused a >25-fold elevation of D-2HG when expressed ubiquitously i ...[more]

PMID: 25398939

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Project description:Coupling immunity and development is essential to ensure survival despite changing internal conditions in the organism. The metamorphosis of the fruit fly represents a striking example of drastic and systemic physiological changes that need to be integrated with the innate immune system. However, the mechanisms that coordinate development and immune cell activity in the transition from larva to adult in Drosophila remain to elucidate. The steroid hormone ecdysone is known to act as a key coordinator of metamorphosis. This hormone activates a nuclear receptor, the Ecdysone Receptor (EcR), which acts as a heterodimer with its partner Ultraspiracle (USP). Together, they activate the transcription of primary response genes, which in turn activate the transcription of a battery of late response genes. We have revealed that regulation of macrophage-like cells (hemocytes) by the steroid hormone ecdysone is essential for an effective innate immune response over metamorphosis. We have shown that in response to ecdysone signalling, hemocytes rapidly up regulate actin dynamics, motility and phagocytosis of apoptotic corpses, and acquire the ability to chemotax to damaged epithelia. Most importantly, individuals lacking ecdysone-activated hemocytes are defective in bacterial phagocytosis and are fatally susceptible to infection by bacteria ingested at larval stages, despite the normal systemic production of antimicrobial peptides. This decrease in survival is comparable to the one observed in pupae lacking immune cells altogether, indicating that ecdysone-regulation is essential to hemocyte immune functions and survival after infection. To better understand the ecdysone regulation of hemocyte activities, we have performed gene expression analysis. In order to identify the genes which expression change at the onset of metamorphosis, we have sorted hemocytes from 3rd instar larvae and from young prepupae and compared their gene expression. Moreover, and in order to identify which genes are regulated by the ecdysone signalling, we have used individuals expressing a dominant negative form of the Ecdysone Receptor specifically in their hemocytes. We have sorted hemocytes from 3rd instar and young prepupae of this genotype to compare their gene expression to the gene expression in larvae and prepupae from the control individuals. Hemocytes were isolated by FACS from selected 3rd instar larvae (at the late feeding stage) and prepupae (from 1h to 2h after puparium formation - APF) corresponding to two different genotypes: individuals w;HmlDeltaGal4, UAS-GFP/+ that express GFP specifically in hemocytes (genotype control), and individuals w;HmlDeltaGal4; UAS-GFP/UAS-EcRB1DN W650A which hemocytes express an Ecdysone Receptor Dominant Negative construct in addition to the GFP (EcRDN). For each of the four conditions we performed three biological replicates.

Dataset Information

Expression from hemocytes misexpressing Idh-R195H vs. controls

Publications

Genetic dissection of leukemia-associated IDH1 and IDH2 mutants and D-2-hydroxyglutarate in Drosophila.

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