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Systems Modeling of the Rho Signaling Network

ABSTRACT: Describing the architecture of robust, nonlinear cell signaling networks is essential to gain a predictive understanding of cellular behavior. The structure of the Drosophila Rho-signaling network, comprised of Rho-family GTPases, RhoGTP Exchange Factors (RhoGEFs), and RhoGTPase Activating Proteins (RhoGAPs), has been particularly difficult to infer due to the highly overlapping function and substrate specificity of network components. We developed a parameterized modeling approach to predict connectivity amongst components of the Rho-signaling network that was driven by hundreds of mRNA expression profiles derived from RNAi-mediated inhibition or overexpression of component genes. Our model incorporated rate kinetics, transcriptional feedback, and noise. We biochemically validated several novel predicted connections, and used this model to predict Rho-signaling response to particular conditions. While functional redundancy is a feature of all signaling systems that often prevents classical genetic methods from elucidating relationships between components, the methods described here provide the basis for describing any complex network architecture. Keywords: Genetic modification, RNAi-mediated gene inhibition 129 samples analyzed. Experiments were peformed in batches of 4 containing 1 control/reference sample (transfection of GFP alone) that was prepared in parallel with experimental samples. There are 30 reference samples. The majority of experiments were replicated 2-6 times.

ORGANISM(S): Drosophila melanogaster

SUBMITTER: Michael Baym

PROVIDER: E-GEOD-18307 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Systems Modeling of the Rho Signaling Network

Project description:Describing the architecture of robust, nonlinear cell signaling networks is essential to gain a predictive understanding of cellular behavior. The structure of the Drosophila Rho-signaling network, comprised of Rho-family GTPases, RhoGTP Exchange Factors (RhoGEFs), and RhoGTPase Activating Proteins (RhoGAPs), has been particularly difficult to infer due to the highly overlapping function and substrate specificity of network components. We developed a parameterized modeling approach to predict connectivity amongst components of the Rho-signaling network that was driven by hundreds of mRNA expression profiles derived from RNAi-mediated inhibition or overexpression of component genes. Our model incorporated rate kinetics, transcriptional feedback, and noise. We biochemically validated several novel predicted connections, and used this model to predict Rho-signaling response to particular conditions. While functional redundancy is a feature of all signaling systems that often prevents classical genetic methods from elucidating relationships between components, the methods described here provide the basis for describing any complex network architecture. Keywords: Genetic modification, RNAi-mediated gene inhibition

2012-12-31 | GSE18307 | GEO

The faint sausage gene encodes a subunit of the spliceosome-activating Prp19 complex and is required for tracheal branching morphogenesis in Drosophila

Project description:Morphogenesis requires the dynamic regulation of gene expression, including transcription, mRNA maturation and translation. Dysfunction of general components of the splicing machinery can cause surprisingly specific phenotypes, but the basis for these cell-type specific effects is not clear. Here we show that the faint sausage (fas) locus, implicated in epithelial morphogenesis and previously reported to encode a secreted immunoglobulin domain protein, in fact encodes a subunit of the Prp19 complex that is essential for efficient pre-mRNA splicing. Loss of zygotic fas function impairs the efficiency of splicing, associated with widespread retention of introns in mature mRNAs and dramatic changes in gene expression. Surprisingly, despite these general effects, zygotic fas mutants show specific defects in tracheal cell migration. Zygotic fas function becomes essential during late embryogenesis when maternally supplied splicing factors decline. We propose that tracheal branching, which relies on dynamic changes in gene expression, is particularly sensitive for efficient spliceosome function. Our results provide an entry point to study functions of splicing during organogenesis and provide a better understanding of specific disease phenotypes associated with mutations in general splicing factors.

2016-11-18 | E-MTAB-5069 | biostudies-arrayexpress

The E3 Ligase CUL3 physically interacts with TANGO10 protein in vivo

Project description:List of protein scores for putative TANGO10 interactors from mass spectrometry analysis of FLAG-tagged TANGO10 using either elav-GAL4 or tim-GAL4 at both ZT10 and ZT 22, as determined using Proteome Discoverer software (ThermoFisher). Fly heads from GAL4 heterozygotes were used as controls. The hits from FLAG-tagged twenty-four (TYF) proteomics were also excluded from the list to increase TANGO10-specificity. Proteins listed are those present in at least one elav-GAL4 sample and at least one tim-GAL4 sample but no negative controls.

2021-11-02 | PXD029326 | Pride

The exon junction complex regulates the splicing of cell polarity gene dlg1 to control Wingless signaling in development

Project description:Wingless (Wg)/Wnt signaling is conserved in all metazoan animals and plays critical roles in development. The Wg/Wnt morphogen reception is essential for signal activation, whose activity is mediated through the receptor complex and a scaffold protein Dishevelled (Dsh). We report here that the exon junction complex (EJC) activity is indispensable for Wg signaling by maintaining an appropriate level of Dsh protein for Wg ligand reception in Drosophila. Transcriptome analyses in Drosophila wing imaginal discs indicate that the EJC controls the splicing of the cell polarity gene disc large 1 (dlg1), whose coding protein directly interacts with Dsh. Genetic and biochemical experiments demonstrate that Dlg1 protein acts independently from its role in cell polarity to protect Dsh protein from lysosomal degradation. More importantly, human orthologous Dlg protein is sufficient to promote Dvl protein stabilization and Wnt signaling activity, thus revealing a conserved regulatory mechanism of Wg/Wnt signaling by Dlg and EJC. whole transcriptome RNA-seq to examine mRNAs extracted from wildtype (i.e. overexpressing lacZ) and pre-EJC-defective (i.e. overexpressing tsu RNAi) wing discs, respectively.

2016-08-19 | E-GEOD-81220 | biostudies-arrayexpress

fly brm knockdown RNA-seq

Project description:Drosophila PBAP complex, a form of SWI/SNF class of complexes, played a important role in metamorphosis. We conducted next-generation sequencing (NGS) to analyse the expression profile in both control and Brm knockdown fly larvae.

2014-05-08 | E-MTAB-1966 | biostudies-arrayexpress

Dm Ladybird over-expression and loss-of-function Expression Profiling

Project description:In order to identify Ladybird mesodermal and heart target genes, we decided to analyse the transcriptional profiling of embryos with a targeted gain and Loss of function approach. Embryos were collected at stages 11 to 15 of embryogenesis corresponding to the lb expression period. Homozygous ectopically expressing or repressing embryos were collected from a large scale cross of UAS-lbe or UAS-RNAi-lbe flies with 24B-Gal4 or Tin-Gal4 flies, in parallel to stage-matched control. Three independent collections were performed. Total RNA was extracted. Ectopically expression and reference samples were hybridized together on GeneChip Drosophila Genome array2. With this approach, we were able to dicover a repertory of genes involved in different aspects of muscle and heart formation showing a multi-step action of this family of identity genes.

2008-02-05 | E-TABM-297 | biostudies-arrayexpress

Transcriptome analysis of Drosophila neural stem cells reveals a transcriptional network for self-renewal.

Project description:Drosophila neuroblasts have emerged as a model for stem cell biology that is ideal for genetic analysis but is limited by the lack of cell-type specific gene expression data. Here, we describe a methodology to isolate large numbers of pure neuroblasts and differentiating neurons that retain both cell cycle and lineage characteristics. We determine transcriptional profiles by mRNA sequencing and identify 28 predicted neuroblast specific transcription factors, which can be arranged in a network containing hubs for Notch signaling, growth control and chromatin regulation. Overexpression and RNAi for these factors identify Klumpfuss as a regulator of self-renewal. We show that loss of Klu function causes premature differentiation while overexpression results in the formation of transplantable brain tumors. Our data represent a valuable resource for Drosophila developmental neurobiology and we describes methodology that can be applied to other invertebrate stem cell lineages as well. comparison of transcriptomes of Drosophila melanogaster larval neuroblasts and their differentiated daughter cells (neurons)

2012-08-21 | E-GEOD-38764 | biostudies-arrayexpress

Transcriptional profiling of Drosophila wing pouch following CR32027 RNAi

Project description:The eukaryotic cell cycle, driven by both transcriptional and post-translational mechanisms, is the central molecular oscillator underlying tissue growth throughout animals. While genome-wide studies have investigated cell cycle-associated transcription in unicellular systems, global patterns of periodic transcription in multicellular tissues remain largely unexplored. Here we define the cell cycle-associated transcriptome of the developing Drosophila wing epithelium and compare it with that of cultured Drosophila S2 cells, revealing a core set of periodic genes as well as a surprising degree of context-specificity in periodic transcription. We further employ RNAi-mediated phenotypic profiling to define functional requirements for over 300 periodic genes, with a focus on those required for cell proliferation in vivo. Finally, we investigate the role of novel genes required for interkinetic nuclear migration. Combined, these findings provide a global perspective on cell cycle control in vivo, and highlight a critical need to understand the context-specific regulation of cell proliferation. Two RNAi lines of CR32027, a non-coding RNA gene identified in this study, are examined for transcriptional changes relative to wt. Transcriptional profiles of two RNAi knockdowns, CR32027-IR1 and CR32027-IR2, are examined in Drosophila wing pouch relative to OreR wt in triplicate by RNA Seq.

2014-03-15 | E-GEOD-54927 | biostudies-arrayexpress

Neprilysins regulate muscle contraction and heart function via cleavage of SERCA-inhibitory micropeptides

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2022-06-01 | PXD027738 | Pride

RNAi profiling by array of Drosophila salivary glands upon NSL3, MCRS2 and MBDR2 RNAi mediated depletion

Project description:Expression profiling of NSL3, MCRS2 and MBDR2 RNAi-mediated depletion in Drosophila salivary glands. This experiment is related to experiment E-MTAB-214

2010-06-25 | E-MEXP-2652 | biostudies-arrayexpress

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