Dataset Information

Genetic screen for regulators of lymph gland homeostasis and hemocyte maturation in Drosophila.

ABSTRACT: Blood cell development in the Drosophila lymph gland is controlled by multiple factors, most of them conserved from flies to mammals. The Drosophila homolog of vertebrate PDCD2, Zfrp8, is required in Drosophila hematopoietic stem cell development. Zfrp8 mutant larvae show a disruption of homeostasis in the lymph gland and vast lymph gland overgrowth. The loss of one copy of Zfrp8 also causes a lymph gland enlargement. This dominant phenotype can be modified by heterozygous mutations in cell-cycle genes and several genes functioning in blood development. To identify additional genes that function in hematopoiesis, we screened a collection of second and third chromosome deficiencies for modifiers of Zfrp8 heterozygous phenotype. Using deficiency mapping, available single gene mutations, and RNAi lines, we identified several novel factors required for lymph gland development and hemocyte differentiation. Distinct lymph gland phenotypes of nine of these genes are reported here for the first time. Importantly, the orthologs of four of them have a role in mammalian blood development and leukemogenesis. Our work has shown that the number of genes regulating normal blood cell development in Drosophila is much larger than expected, and that the complex molecular mechanisms regulating hemocyte differentiation are comparable to those in vertebrates.

SUBMITTER: Tan KL

PROVIDER: S-EPMC3291509 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Genetic screen for regulators of lymph gland homeostasis and hemocyte maturation in Drosophila.

Tan Kai Li KL Goh Siow Chong SC Minakhina Svetlana S

G3 (Bethesda, Md.) 20120301 3

Blood cell development in the Drosophila lymph gland is controlled by multiple factors, most of them conserved from flies to mammals. The Drosophila homolog of vertebrate PDCD2, Zfrp8, is required in Drosophila hematopoietic stem cell development. Zfrp8 mutant larvae show a disruption of homeostasis in the lymph gland and vast lymph gland overgrowth. The loss of one copy of Zfrp8 also causes a lymph gland enlargement. This dominant phenotype can be modified by heterozygous mutations in cell-cycl ...[more]

PMID: 22413093

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Project description:Large-scale RNAi-based screens are playing a critical role in defining sets of genes that regulate specific cellular processes. Numerous screens have been completed and in some cases more than one screen has examined the same cellular process, enabling a direct comparison of the genes identified in separate screens. Surprisingly, the overlap observed between the results of similar screens is low, suggesting that RNAi screens have relatively high levels of false positives, false negatives, or both.We re-examined genes that were identified in two previous RNAi-based cell cycle screens to identify potential false positives and false negatives. We were able to confirm many of the originally observed phenotypes and to reveal many likely false positives. To identify potential false negatives from the previous screens, we used protein interaction networks to select genes for re-screening. We demonstrate cell cycle phenotypes for a significant number of these genes and show that the protein interaction network is an efficient predictor of new cell cycle regulators. Combining our results with the results of the previous screens identified a group of validated, high-confidence cell cycle/cell survival regulators. Examination of the subset of genes from this group that regulate the G1/S cell cycle transition revealed the presence of multiple members of three structurally related protein complexes: the eukaryotic translation initiation factor 3 (eIF3) complex, the COP9 signalosome, and the proteasome lid. Using a combinatorial RNAi approach, we show that while all three of these complexes are required for Cdk2/Cyclin E activity, the eIF3 complex is specifically required for some other step that limits the G1/S cell cycle transition.Our results show that false positives and false negatives each play a significant role in the lack of overlap that is observed between similar large-scale RNAi-based screens. Our results also show that protein network data can be used to minimize false negatives and false positives and to more efficiently identify comprehensive sets of regulators for a process. Finally, our data provides a high confidence set of genes that are likely to play key roles in regulating the cell cycle or cell survival.

Dataset Information

Genetic screen for regulators of lymph gland homeostasis and hemocyte maturation in Drosophila.

Publications

Genetic screen for regulators of lymph gland homeostasis and hemocyte maturation in Drosophila.

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