Tissue overgrowth induced by coexpression of the progenitor genes hth/MEIS1 and tsh/TSHZ results from an imbalance in the estrogen response pathway in Drosophila
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ABSTRACT:
ORGANISM(S): Drosophila melanogaster
PROVIDER: GSE65252 | GEO | 2017/08/31
SECONDARY ACCESSION(S): PRJNA273496
REPOSITORIES: GEO
Similar Datasets
Project description:Analysis of third instar eye-antennal Drosophila imaginal discs with forced expression of hth, tsh or hth+tsh in the eye using an eye-specific GAL4 driver (optix2.3-GAL4). Forced maintenance of hth+tsh expression (but not of any of the two alone) results in overgrowth and aberrant cell differentiation. Results provide insight into new targets of hth+tsh.
2017-08-31 | GSE65251 | GEO
Project description:Analysis of third instar eye-antennal Drosophila imaginal discs with forced expression of hth, tsh or hth+tsh in the eye using an eye-specific GAL4 driver (optix2.3-GAL4). Forced maintenance of hth+tsh expression (but not of any of the two alone) results in overgrowth and aberrant cell differentiation. Results provide insight into new targets of hth+tsh.
2017-08-31 | GSE65250 | GEO
Project description:Tissue overgrowth induced by coexpression of the progenitor genes hth/MEIS1 and tsh/TSHZ results from an imbalance in the estrogen response pathway in Drosophila
| PRJNA273496 | ENA
Project description:Restless Legs Syndrome (RLS) is a genetically complex neurological disorder in which overlapping genetic risk factors may contribute to the diversity and heterogeneity of the symptoms. The main goal of the study was to investigate, through analysis of heart rate variability (HRV), whether in RLS patients the MEIS1 polymorphism at risk influences the sympathovagal regulation in different sleep stages. Sixty-four RLS patients with periodic leg movement index above 15 per hour, and 38 controls underwent one night of video-polysomnographic recording. HRV in the frequency- and time- domains was analyzed during nighttime sleep. All RLS patients were genotyped, and homozygotes for rs2300478 in the MEIS1 locus were used for further analysis. Comparison of the sympathovagal pattern of RLS patients to control subjects did not show significant differences after adjustments for confounding factors in frequency-domain analyses, but showed an increased variability during N2 and N3 stages in time-domain analyses in RLS patients. Sorting of RLS patients according to MEIS1 polymorphism reconfirmed the association between MEIS1 and PLMS, and showed a significant increased sympathovagal balance during N3 stage in those homozygotes for the risk allele. RLS patients should be considered differently depending on MEIS1 genotype, some being potentially at risk for cardiovascular disorders.
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Project description:In Drosophila, protein trap strategies provide powerful approaches for the generation of tagged proteins expressed under endogenous control. Here, we describe expression and functional analysis to evaluate new Ubx and hth protein trap lines generated by the Cambridge Protein Trap project. Both protein traps exhibit spatial and temporal expression patterns consistent with the reported endogenous pattern in the embryo. In imaginal discs, Ubx-YFP is expressed throughout the haltere and 3rd leg imaginal discs, while Hth-YFP is expressed in the proximal regions of haltere and wing discs but not in the pouch region. The Ubx (CPTI000601) line is semilethal as a homozygote. No T3/A1 to T2 transformations were observed in the embryonic cuticle or the developing midgut. The homozygous survivors, however, exhibit a weak haltere phenotype with a few wing-like marginal bristles on the haltere capitellum. Although hth (CPTI000378) is completely lethal as a homozygote, the hth (CPTI000378) /hth (C1) genotype is viable. Using a hth deletion (Df(3R)BSC479) we show that hth (CPTI000378) /Df(3R)BSC479 adults are phenotypically normal. No transformations were observed in hth (CPTI000378), hth (CPTI000378) /hth (C1), or hth (CPTI000378) /Df(3R)BSC479 embryonic cuticles. We have successfully characterised the Ubx-YFP and Hth-YFP protein trap lines demonstrating that the tagged proteins show appropriate expression patterns and produce at least partially functional proteins.
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Project description:The transcription factor forkhead box N4 (Foxn4) is a key regulator in a variety of biological processes during development. In particular, Foxn4 plays an essential role in the genesis of horizontal and amacrine neurons from neural progenitors in the vertebrate retina. Although the functions of Foxn4 have been well established, the transcriptional regulation of Foxn4 expression during progenitor cell differentiation remains unclear. Here, we report that an evolutionarily conserved 129 bp noncoding DNA fragment (Foxn4CR4.2 or CR4.2), located ∼26 kb upstream of Foxn4 transcription start site, functions as a cis-element for Foxn4 regulation. CR4.2 directs gene expression in Foxn4-positive cells, primarily in progenitors, differentiating horizontal and amacrine cells. We further determined that the gene regulatory activity of CR4.2 is modulated by Meis1 binding motif, which is bound and activated by Meis1 transcription factor. Deletion of the Meis1 binding motif or knockdown of Meis1 expression abolishes the gene regulatory activity of CR4.2. In addition, knockdown of Meis1 expression diminishes the endogenous Foxn4 expression and affects cell lineage development. Together, we demonstrate that CR4.2 and its interacting Meis1 transcription factor play important roles in regulating Foxn4 expression during early retinogenesis. These findings provide new insights into molecular mechanisms that govern gene regulation in retinal progenitors and specific cell lineage development.
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Project description:Our goal is to characterize the innate immune response against the early stage of tumor development. For this, animal models where genetic changes in specific cells and tissues can be performed in a controlled way have become increasingly important, including the fruitfly Drosophila melanogaster. Many tumor mutants in Drosophila affect the germline and, as a consequence, also the immune system itself, making it difficult to ascribe their phenotype to a specific tissue. Only during the past decade, mutations have been induced systematically in somatic cells to study the control of tumorous growth by neighboring cells and by immune cells. Here we show that upon ectopic expression of a dominant-active form of the Ras oncogene (Ras(V12)), both imaginal discs and salivary glands are affected. Particularly, the glands increase in size, express metalloproteinases and display apoptotic markers. This leads to a strong cellular response, which has many hallmarks of the granuloma-like encapsulation reaction, usually mounted by the insect against larger foreign objects. RNA sequencing of the fat body reveals a characteristic humoral immune response. In addition we also identify genes that are specifically induced upon expression of Ras(V12). As a proof-of-principle, we show that one of the induced genes (santa-maria), which encodes a scavenger receptor, modulates damage to the salivary glands. The list of genes we have identified provides a rich source for further functional characterization. Our hope is that this will lead to a better understanding of the earliest stage of innate immune responses against tumors with implications for mammalian immunity.
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Project description:Synaptic terminals are known to expand and contract throughout an animal's life. The physiological constraints and demands that regulate appropriate synaptic growth and connectivity are currently poorly understood. In previous work, we identified a Drosophila model of lysosomal storage disease (LSD), spinster (spin), with larval neuromuscular synapse overgrowth. Here we identify a reactive oxygen species (ROS) burden in spin that may be attributable to previously identified lipofuscin deposition and lysosomal dysfunction, a cellular hallmark of LSD. Reducing ROS in spin mutants rescues synaptic overgrowth and electrophysiological deficits. Synapse overgrowth was also observed in mutants defective for protection from ROS and animals subjected to excessive ROS. ROS are known to stimulate JNK and fos signaling. Furthermore, JNK and fos in turn are known potent activators of synapse growth and function. Inhibiting JNK and fos activity in spin rescues synapse overgrowth and electrophysiological deficits. Similarly, inhibiting JNK, fos, and jun activity in animals with excessive oxidative stress rescues the overgrowth phenotype. These data suggest that ROS, via activation of the JNK signaling pathway, are a major regulator of synapse overgrowth. In LSD, increased autophagy contributes to lysosomal storage and, presumably, elevated levels of oxidative stress. In support of this suggestion, we report here that impaired autophagy function reverses synaptic overgrowth in spin. Our data describe a previously unexplored link between oxidative stress and synapse overgrowth via the JNK signaling pathway.
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Project description:BACKGROUND:Investigating how epigenetic information is transmitted through the mammalian germline is the key to understanding how this information impacts on health and disease susceptibility in offspring. EED is essential for regulating the repressive histone modification, histone 3 lysine 27 tri-methylation (H3K27me3) at many developmental genes. RESULTS:In this study, we used oocyte-specific Zp3-Cre recombinase (Zp3Cre) to delete Eed specifically in mouse growing oocytes, permitting the study of EED function in oocytes and the impact of depleting EED in oocytes on outcomes in offspring. As EED deletion occurred only in growing oocytes and females were mated to normal wild type males, this model allowed the study of oocyte programming without confounding factors such as altered in utero environment. Loss of EED from growing oocytes resulted in a significant overgrowth phenotype that persisted into adult life. Significantly, this involved increased adiposity (total fat) and bone mineral density in offspring. Similar overgrowth occurs in humans with Cohen-Gibson (OMIM 617561) and Weaver (OMIM 277590) syndromes, that result from de novo germline mutations in EED or its co-factor EZH2, respectively. Consistent with a role for EZH2 in human oocytes, we demonstrate that de novo germline mutations in EZH2 occurred in the maternal germline in some cases of Weaver syndrome. However, deletion of Ezh2 in mouse oocytes resulted in a distinct phenotype compared to that resulting from oocyte-specific deletion of Eed. CONCLUSIONS:This study provides novel evidence that altering EED-dependent oocyte programming leads to compromised offspring growth and development in the next generation.
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