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Multiple functions for Eya3 in mammalian organism

ABSTRACT: The important function of Eya (eyes absent) in eye development of D.melanogaster is well known, the function of its mammalian orthologs Eya1-4 is only partially understood. Yet, no phenotype for Eya2 and Eya3 in humans or mouse have been described. In our study we analysed new Eya-deficient mouse model generated by insertional mutagenesis. Expression analysis of Eya3 by in-situ hybridizations and β-Gal-staining revealed a broad expression of the gene throughout development, e.g. in brain, eyes, branchial arches, somites and limbs. This diverse expression pattern suggests pleiotropic effects of Eya3 in mammalian organisms. In contrast to D. melanogaster, a close examination of the eye by various methods did not show any obvious ocular defects in mutant animals. A broad phenotypical characterization of homozygous mutants displayed decreased body weight and body length. Additionally, behavioral changes as a educed forward locomotor activity and altered exploratory behaviour were identified. A significant reduction of forelimb grip strength and an impairment of cardiac processes in Eya3-/- mice suggest a role for Eya3 in muscle development and heart function. Our results implicate that Eya3 plays various roles outside the eye with effects particularly on heart and muscle function in the mouse. Keywords: Eya3-deficient mice, cDNA microarrays, brain, heart, muscle

ORGANISM(S): Mus musculus

PROVIDER: GSE9999 | GEO | 2008/12/17

SECONDARY ACCESSION(S): PRJNA104023

REPOSITORIES: GEO

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Multiple functions for Eya3 in mammalian organism

Project description:The important function of Eya (eyes absent) in eye development of D.melanogaster is well known, the function of its mammalian orthologs Eya1-4 is only partially understood. Yet, no phenotype for Eya2 and Eya3 in humans or mouse have been described. In our study we analysed new Eya-deficient mouse model generated by insertional mutagenesis. Expression analysis of Eya3 by in-situ hybridizations and M-NM-2-Gal-staining revealed a broad expression of the gene throughout development, e.g. in brain, eyes, branchial arches, somites and limbs. This diverse expression pattern suggests pleiotropic effects of Eya3 in mammalian organisms. In contrast to D. melanogaster, a close examination of the eye by various methods did not show any obvious ocular defects in mutant animals. A broad phenotypical characterization of homozygous mutants displayed decreased body weight and body length. Additionally, behavioral changes as a educed forward locomotor activity and altered exploratory behaviour were identified. A significant reduction of forelimb grip strength and an impairment of cardiac processes in Eya3-/- mice suggest a role for Eya3 in muscle development and heart function. Our results implicate that Eya3 plays various roles outside the eye with effects particularly on heart and muscle function in the mouse. Keywords: Eya3-deficient mice, cDNA microarrays, brain, heart, muscle analysis of 4 Eya3 mutant mice versus a pool of 5 wildtype animals; brain, heart, and muscle; 8 hybridisations for each tissue: two technical replicates for each mutant animal including one dye-swap experiments

2008-12-17 | E-GEOD-9999 | biostudies-arrayexpress

Identification of Transcriptional Targets Dual Functions Transcription Factor/Phosphatase Eyes Absent

Project description:Drosophila eye specification an development relies on a collection of transcription factors termed the retinal determination gene network (RDGN). Two members of this network, Eyes absent (EYA) and Sine oculis (SO), form a transcriptional complex in which EYA provides the transactivation function while SO provides the DNA binding activity. EYA also function as a protein tyrosine phosphatase, raising the question of whether transcriptional output is dependent or independent of phosphatase activity. To explore this, we used microarrays together with binding site analysis, quantitative real-time PCR, chromatin immunoprecipitation, genetics, and in vivo expression analysis to identify new EYA-SO targets. In parallel, we examined the expression profiles of tissue expressing phosphatase mutant eya and found that reducing phosphatase activity did not globally impair transcriptional output. Among the targets identified by our analysis was the cell cycle regulatory gene, string (stg), suggesting that EYA and SO may influence cell proliferation through transcriptional regulation of stg. Future investigation into the regulation of stg and other EYA-SO targets identified in this study will help elucidate the transcriptional circuitries whereby output from the RDGN integrates with other signaling inputs to coordinate retinal development. Keywords: gain of function, expression comparison

2007-11-07 | GSE9538 | GEO

Transcription profiling of Drosophila tissue expressing phosphatase mutant eya shows that reducing phosphatase activity did not globally impair transcriptional output

2008-03-13 | E-GEOD-9538 | biostudies-arrayexpress

Genome-wide mapping of Collier in vivo binding sites highlights its hierarchical position in different transcription regulatory networks

Project description:Collier, the single Drosophila COE (Collier/EBF/Olf-1) transcription factor, is required in several developmental processes, including head patterning and specification of muscle and neuron identity during embryogenesis. To identify direct Collier (Col) targets in different cell types, we used ChIP-seq to map Col binding sites throughout the genome, at mid-embryogenesis. In vivo Col binding peaks were associated to 415 potential direct target genes. Gene Ontology analysis revealed a strong enrichment in proteins with DNA binding and/or transcription-regulatory properties. Characterization of a selection of candidates, using transgenic CRM-reporter assays, identified direct Col targets in dorso-lateral somatic muscles and specific neuron types in the central nervous system. These data brought new evidence that Col direct control of the expression of the transcription regulators apterous and eyes-absent (eya) is critical to specifying neuronal identities. They also showed that cross-regulation between col and eya in muscle progenitor cells is required for specification of muscle identity, revealing a new parallel between the myogenic regulatory networks operating in Drosophila and vertebrates. Col regulation of eya, both in specific muscle and neuronal lineages, may illustrate one mechanism behind the evolutionary diversification of Col biological roles.

2015-08-03 | GSE67805 | GEO

Proteomic analysis of Eya3 binding partners

Project description:Eyes absent homolog 3 (EYA3) is a transcriptional cofactor that is known to partner with the sine oculis homeobox (SIX) family to regulate gene expression. In this study, we characterized a novel splice isoform of EYA3, including the alternative cassette exon 7 (EYA3+ex7), that becomes more highly expressed compared to the isoform lacking exon 7 (EYA3Δex7) during muscle cell differentiation and muscle development. This developmentally-regulated splicing pattern was evolutionarily conserved in humans, mice, rats, chickens, and zebrafish. We found that EYA3 isoforms are vital to proliferation and differentiation of myoblasts in a cell culture model of myogenesis. To understand the underlying mechanism, we defined the transcriptional networks controlled by EYA3 through RNA-sequencing of EYA3 depleted cells. We then hypothesized that binding partners of EYA3+ex7 and EYA3Δex7 might contribute to the mechanism by which they regulate transcription. An affinity-purification mass spectrometry approach was used to identify binding partners of EYA3 isoforms by heterologous expression of hemagglutinin (HA) tagged isoforms in HEK293T cells. 26 binding partners (defined as those with log2(FC) > 1 and p < 0.05 compared to HA epitope tag control) were shared among the EYA3 isoforms, including five transcription factors: zinc finger and BTB domain containing 1 (ZBTB1), tumor protein p53 (TP53), SIX5, SIX2, and SIX4. We next demonstrated that ZBTB1 and SIX4 share overlapping transcriptional targets with EYA3, indicating that EYA3 partners with ZBTB1 or SIX4 to regulate gene expression. Three and thirteen unique binding partners were discovered for EYA3Δex7 and EYA3+ex7, respectively. Therefore, inclusion of Eya3 exon 7 may allow for unique interactions and contribute to functions of EYA3+ex7 that are distinct from EYA3Δex7. This dataset includes affinity purified data for Eya3 isoforms in HEK293T cells.

2023-10-13 | PXD037572 | Pride

Genome-wide mapping of Collier in vivo binding sites highlights its hierarchical position in different transcription regulatory networks

2015-08-03 | E-GEOD-67805 | biostudies-arrayexpress

The Eyes Absent family members EYA4 and EYA1 promote PLK1 activation and successful mitosis through tyrosine dephosphorylation: siEYA4 pY IP-MS

Project description:The Eyes Absent family of proteins (EYA1-4) are a biochemically unique group of tyrosine phosphatases known to be tumour promoting across a range of cancer types. To date, the molecular targets of EYA phosphatase activity remain largely uncharacterised. Here, we identify Polo-like kinase 1 (PLK1) as a direct interactor and phosphatase substrate of both EYA4 and EYA1, with pY445 on PLK1 being the primary target site. EYA-mediated dephosphorylation of PLK1 in the G2 phase of the cell cycle is required for centrosome maturation, PLK1 localization to centrosomes, and polo-box domain (PBD) dependent interactions between PLK1 and the PLK1-activating proteins BORA and CEP192. Molecular dynamics simulations support the rationale that pY445 confers a structural impairment to PBD-substrate interactions that is relieved by EYA-mediated dephosphorylation. Depletion of EYA4 or EYA1, or chemical inhibition of EYA phosphatase activity, dramatically reduces PLK1 activation, causing mitotic defects and cell death. Overall, we have characterized a novel phosphotyrosine signalling network governing PLK1 and mitosis. This work provides a mechanism of cell killing for EYA phosphatase inhibitors with important therapeutic implications.

2024-02-26 | PXD036430 | Pride

Development of a benzarone derivative as targeted therapy for SHH-medulloblastoma [Day 1]

Project description:Medulloblastoma is one of the most common malignant brain tumors of children, and 30% of medulloblastomas are driven by gain-of-function genetic lesions in the Sonic hedgehog (SHH) signaling pathway. Eyes Absent (EYA1), a haloacid dehalogenase (HAD) phosphatase and co-transcription factor, is critical for tumorigenesis and proliferation of SHH-medulloblastoma (SHH-MB). Benzarone and benzbromarone have been identified as allosteric inhibitors for the Eya proteins. Using benzarone as a point of departure, we developed a panel of 35 derivatives, and identified one new compound, DS-1-38, that functions as an Eya-antagonist, opposes SHH-signaling, inhibits SHH-MB growth in vitro and in vivo, shows excellent brain penetrance and increases the lifespan of mice predisposed to fatal SHH-MB. Our data suggest that DS-1-38 provides a path for developing targeted therapeutic for pediatric SHH-MB.

2023-12-21 | GSE229192 | GEO

Development of a benzarone derivative as targeted therapy for SHH-medulloblastoma [Day 5]

2023-12-21 | GSE229176 | GEO

Zebrafish (Danio rerio) 72hpf, WT control vs. MO-Prpf31 injected

Project description:Transcriptional profiling performed from total eye RNA extracts of wildtype control fishes versus Prpf31 morpholino injected larvae (at ~72hpf) two-condition experiment: wildtype zebrafish versus MO-Prpf31 injected zebrafish eye RNA; 6 replicates each (extraction from 6 pools (~200 eyes each) of controls and 6 pools MO-Prpf31 (~200 eyes each))

2010-05-06 | E-GEOD-20424 | biostudies-arrayexpress

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