A requirement for dual-specificity phosphatase 6 in zebrafish gametogenesis
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ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE102793 | GEO | 2018/02/12
REPOSITORIES: GEO
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Project description:BACKGROUND:Signaling cascades, such as the extracellular signal-regulated kinase (ERK) pathway, play vital roles in early vertebrate development. Signals through these pathways are initiated by a growth factor or hormone, are transduced through a kinase cascade, and result in the expression of specific downstream genes that promote cellular proliferation, growth, or differentiation. Tight regulation of these signals is provided by positive or negative modulators at varying levels in the pathway, and is required for proper development and function. Two members of the dual-specificity phosphatase (Dusp) family, dusp6 and dusp2, are believed to be negative regulators of the ERK pathway and are expressed in both embryonic and adult zebrafish, but their specific roles in embryogenesis remain to be fully understood. RESULTS:Using CRISPR/Cas9 genome editing technology, we generated zebrafish lines harboring germ line deletions in dusp6 and dusp2. We do not detect any overt defects in dusp2 mutants, but we find that approximately 50% of offspring from homozygous dusp6 mutants do not proceed through embryonic development. These embryos are fertilized, but are unable to proceed past the first zygotic mitosis and stall at the 1-cell stage for several hours before dying by 10 h post fertilization. We demonstrate that dusp6 is expressed in gonads of both male and female zebrafish, suggesting that loss of dusp6 causes defects in germ cell production. Notably, the 50% of homozygous dusp6 mutants that complete the first cell division appear to progress through embryogenesis normally and give rise to fertile adults. CONCLUSIONS:The fact that offspring of homozygous dusp6 mutants stall prior to activation of the zygotic genome, suggests that loss of dusp6 affects gametogenesis and/or parentally-directed early development. Further, since only approximately 50% of homozygous dusp6 mutants are affected, we postulate that ERK signaling is tightly regulated and that dusp6 is required to keep ERK signaling within a range that is permissive for proper embryogenesis. Lastly, since dusp6 is expressed throughout zebrafish embryogenesis, but dusp6 mutants do not exhibit defects after the first cell division, it is possible that other regulators of the ERK pathway compensate for loss of dusp6 at later stages.
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Project description:Most cases of acquired hearing loss are due to degeneration and subsequent loss of cochlear hair cells. Whereas mammalian hair cells are not replaced when lost, in zebrafish, they constantly renew and regenerate after injury. However, the molecular mechanism among this difference remains unknown. Dual-specificity phosphatase 14 (DUSP14) is an important negative modulator of mitogen-activated protein kinase (MAPK) signaling pathways. Our study was to investigate the effects of DUSP14 on supporting cell development and hair cell regeneration and explore the potential mechanism. Our results showed that dusp14 gene is highly expressed in zebrafish developing neuromasts and otic vesicles. Behavior analysis showed that dusp14 deficiency resulted in hearing defects in zebrafish larvae, which were reversed by dusp14 mRNA treatment. Moreover, knockdown of dusp14 gene caused a significant decrease in the number of neuromasts and hair cells in both neuromast and otic vesicle, mainly due to the inhibition of the proliferation of supporting cells, which results in a decrease in the number of supporting cells and ultimately in the regeneration of hair cells. We further found significant changes in a series of MAPK pathway genes through transcriptome sequencing analysis of dusp14-deficient zebrafish, especially mapk12b gene in p38 signaling. Additionally, inhibiting p38 signaling effectively rescued all phenotypes caused by dusp14 deficiency, including hair cell and supporting cell reduction. These results suggest that DUSP14 might be a key gene to regulate supporting cell development and hair cell regeneration and is a potential target for the treatment of hearing loss.
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Project description:identification of differentially expressed genes in hoxb1b homozygous mutant hindbrain when compared to wildtype in zebrafish
2018-07-15 | GSE113398 | GEO
Project description:identification of differentially expressed genes in gas6 homozygous mutant hindbrain when compared to wildtype hindbrain in zebrafish
2018-07-15 | GSE113396 | GEO
Project description:Goal of the experiment was to assess the differences in gene expression between zygotic rnf2 mutant zebrafish embryos and wildtype embryos at 3 dpf. The goal of ChIP-sequencing of wildtype embryos at 3 dpf is to link deregulation in gene expression to the Rnf2 occupancy in the wildtype situation and check the overlap between Rnf2 and H3K27me3. The RNA-sequencing of single hearts was performed to assess differences in gene expression between zygotic rn2 mutants hearts and wildtype hearts at 3 different stages (1, 2, 3 dpf)
2019-03-13 | GSE114038 | GEO
Project description:Regulation of p53 phosphorylation is critical to control its stability and biological activity. Dual-specificity phosphatase 26 (DUSP26) is a brain phosphatase highly overexpressed in neuroblastoma, which has been implicated in dephosphorylating phospho-Ser20 and phospho-Ser37 in the p53 transactivation domain. In this paper, we report the 1.68 Å crystal structure of a catalytically inactive mutant (Cys152Ser) of DUSP26 lacking the first 60 N-terminal residues (ΔN60-C/S-DUSP26). This structure reveals the architecture of a dual-specificity phosphatase domain related in structure to Vaccinia virus VH1. DUSP26 adopts a closed conformation of the protein tyrosine phosphatase (PTP)-binding loop, which results in an unusually shallow active site pocket and buried catalytic cysteine. A water molecule trapped inside the PTP-binding loop makes close contacts both with main chain and with side chain atoms. The hydrodynamic radius (R(H)) of ΔN60-C/S-DUSP26 measured from velocity sedimentation analysis (R(H) ∼ 22.7 Å) and gel filtration chromatography (R(H) ∼ 21.0 Å) is consistent with an ∼18 kDa globular monomeric protein. Instead in crystal, ΔN60-C/S-DUSP26 is more elongated (R(H) ∼ 37.9 Å), likely because of the extended conformation of C-terminal helix α9, which swings away from the phosphatase core to generate a highly basic surface. As in the case of phosphatase MKP-4, we propose that a substrate-induced conformational change, possibly involving rearrangement of helix α9 with respect to the phosphatase core, allows DUSP26 to adopt a catalytically active conformation. The structural characterization of DUSP26 presented in this paper provides the first atomic insight into this disease-associated phosphatase.
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Project description:Goal of the experiment was to assess the differences in gene expression between maternal zygotic ezh2 mutant zebrafish embryos and wildtype embryos at 0 and 3.3 hpf.
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Project description:transcriptomic data for 48 hpf Wildtype, slincRosu3 (sg6; slincR +18 bp mutant) and BigD (slincR -131 bp mutant) zebrafish embryos developmentally exposed to TCDD.
2023-08-08 | GSE222975 | GEO
Project description:Mitogen-activated protein kinases are inactivated by dual specificity phosphatases (DUSPs), whose activities are tightly regulated during cell differentiation. Using knockdown screening and single-cell transcriptional analysis, we determined that DUSP4 is the phosphatase that specifically inactivates p38 kinase for the promotion of megakaryocyte (Mk) differentiation. Mechanistically, PRMT1-mediated methylation of DUSP4 triggers its ubiquitinylation by an E3 ligase HUWE1. Interestingly, the mechanistic axis of the DUSP4 degradation and p38 activation is also associated with a transcriptional signature of immune activation in Mk cells. In the context of thrombocytopenia observed in myelodysplastic syndromes (MDS), we demonstrated that high levels of p38 MAPK and PRMT1 are associated with low platelet counts and adverse prognosis, while pharmacological inhibition of p38 MAPK or PRMT1 stimulates megakaryopoiesis. These findings provide mechanistic insights into the role of the PRMT1-DUSP4-p38 axis on Mk differentiation and present a targeting strategy for treatment of thrombocytopenia associated with MDS.
2021-05-12 | GSE174261 | GEO
Project description:The mitogen-activated protein kinase (MAPK) p38 pathway is reported to regulate macrophage responses to lipopolysaccharide (LPS) at least partly via the phosphorylation of the mRNA-destabilizing factor tristetraprolin (TTP). LPS-activated MAPK p38 phosphorylates and activates the downstream kinase MAPK-activated protein kinase 2 (MK2), which then phosphorylates serines 52 and 178 of TTP, resulting in loss of mRNA-destabilizing activity. As a consequence, mRNAs that contain binding sites for TTP are stabilized in a manner that is acutely sensitive to the activity of the MAPK p38 pathway. Dual specificity phosphatase 1 (DUSP1) dephosphorylates and inactivates MAPK p38. Dusp1-/- macrophages overexpress a number of pro-inflammatory mediators, but their genome-wide responses to LPS have not yet been described in detail. Dusp1-/- mice are exceptionally sensitive to a wide variety of inflammatory challenges, including experimental models of endotoxemia or sepsis. It has been suggested (but not yet proven) that DUSP1 controls the inflammatory response of macrophages in part via the regulation of MAPK p38 activity and TTP phosphorylation status. We generated a mouse knock-in strain, in which codons 52 and 178 of the endogenous Zfp36 gene (which encodes TTP) were mutated to alanine codons. The mutation gives rise to a constitutively active form of TTP, which cannot be inactivated via the p38 MAPK pathway. The Zfp36aa/aa strain was back-crossed against C57/BL6 for > 10 generations. We also generated a double-targeted strain in which the Zfp36 mutation was combined with disruption of the Dusp1 gene. This expression array describes LPS responses of primary mouse bone marrow-derived macrophages of four genotypes, and closely matched genetic background: wild type (Dusp1+/+ : Zfp36+/+); TTP mutant (Zfp36aa/aa); DUSP1 knock out (Dusp1-/-); and double targeted (Dusp1-/- : Zfp36aa/aa). The data provide a comprehensive picture of the impact of Dusp1 deletion or TTP mutation on the responses of primary macrophages to LPS. They also demonstrate that the excessive inflammatory responses of Dusp1-/- macrophages are largely a consequence of the phosphorylation and inactivation of TTP. Genome wide expression profiles of wild type, Dusp1-/-, Zfp36aa/aa and Dusp1-/-/Zfp36aa/aa M-CSF derived macrophages, stimulated with LPS for 1 or 4 hours
2015-05-15 | E-GEOD-68449 | biostudies-arrayexpress