Wingless Signaling InducesnautilusExpression in the Ventral Mesoderm of theDrosophilaEmbryo

Ranganayakulu, Gogineni; Schulz, Robert A.; Olson, Eric N.

doi:10.1006/dbio.1996.9987

Cited by 210 publications

(149 citation statements)

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“…1d), which is similar to mitochondrial targeted standard GFP as reported previously (33). We also generated UAS-MitoTimer transgenic flies and crossed with Mef2-Gal4 transgenic flies to generate Mef2-Gal4ϾUAS-MitoTimer flies with muscle expression (34). Confocal microscopy showed mitochondrial structure identical to that obtained in Mef2-Gal4ϾUAS-Mito-GFP flies not only in adult heart tube ( Fig.…”

Section: Mitotimer Protein Targets To Mitochondria and Displayssupporting

confidence: 82%

A Novel MitoTimer Reporter Gene for Mitochondrial Content, Structure, Stress, and Damage in Vivo

Laker

Ryall

et al. 2014

Journal of Biological Chemistry

214

247

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Background: Mitochondrial health is difficult to assess in vivo. Results: We have generated a reporter gene, MitoTimer, which targets mitochondria, and fluoresces green and shifts to red when oxidized, for assessment of mitochondrial content, structure, stress, and damage under physiological and pathological conditions. Conclusion: MitoTimer is useful for assessment of mitochondrial health in vivo. Significance: MitoTimer could advance mitochondrial research in multiple disciplines.

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Section: Mitotimer Protein Targets To Mitochondria and Displayssupporting

confidence: 82%

A Novel MitoTimer Reporter Gene for Mitochondrial Content, Structure, Stress, and Damage in Vivo

Laker

Ryall

et al. 2014

Journal of Biological Chemistry

214

247

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“…Based on our observation that cardiac deletion of MED13 confers an obese phenotype and that cardiac-specific overexpression of MED13 prevents obesity in mice (4), we examined whether muscle expression of MED13, encoded by skd, regulates fat accumulation in Drosophila. We performed RNAimediated knockdown experiments using the UAS/Gal4 system and expressed UAS-RNAi targeting skd mRNA with the Mef2-Gal4 driver, which directs the expression of UAS constructs in somatic, cardiac, and visceral muscle tissues (18)(19)(20)(21). By 3 wk of age, we observed increased abdominal fat bodies in adult Mef2>skd RNAi flies (Fig.…”

Section: Resultsmentioning

confidence: 95%

Heart- and muscle-derived signaling system dependent on MED13 and Wingless controls obesity in Drosophila

Lee

Bassel‐Duby

Olson

2014

Proc. Natl. Acad. Sci. U.S.A.

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Obesity develops in response to an imbalance of energy homeostasis and whole-body metabolism. Muscle plays a central role in the control of energy homeostasis through consumption of energy and signaling to adipose tissue. We reported previously that MED13, a subunit of the Mediator complex, acts in the heart to control obesity in mice. To further explore the generality and mechanistic basis of this observation, we investigated the potential influence of MED13 expression in heart and muscle on the susceptibility of Drosophila to obesity. Here, we show that heart/muscle-specific knockdown of MED13 or MED12, another Mediator subunit, increases susceptibility to obesity in adult flies. To identify possible muscle-secreted obesity regulators, we performed an RNAi-based genetic screen of 150 genes that encode secreted proteins and found that Wingless inhibition also caused obesity. Consistent with these findings, muscle-specific inhibition of Armadillo, the downstream transcriptional effector of the Wingless pathway, also evoked an obese phenotype in flies. Epistasis experiments further demonstrated that Wingless functions downstream of MED13 within a muscle-regulatory pathway. Together, these findings reveal an intertissue signaling system in which Wingless acts as an effector of MED13 in heart and muscle and suggest that Wingless-mediated cross-talk between striated muscle and adipose tissue controls obesity in Drosophila. This signaling system appears to represent an ancestral mechanism for the control of systemic energy homeostasis.O besity is a systemic disorder caused by an energy imbalance in which energy input exceeds energy utilization, resulting in accumulation of excess body fat. Muscle plays a central role in systemic energy homeostasis by consuming nutrients and signaling in an endocrine manner to other tissues (1-3). Thus, there has been intense interest in identifying secreted factors from muscle that modulate the function of adipose tissue.Previously, we reported that cardiac deletion of MED13, a subunit of the Mediator complex, increases susceptibility to obesity in mice whereas cardiac overexpression of MED13 confers a lean phenotype (4), revealing an unforeseen function of the heart as a systemic regulator of energy homeostasis. The Mediator is a conserved multisubunit complex that mediates the interaction between RNA polymerase II and transcription factors and therefore governs transcription in all eukaryotes (5). MED13 and MED12 are among four subunits of the auxiliary kinase module, which confers additional regulatory functions to the Mediator complex (6). Expression profiling of yeast mutants or gene-depleted Drosophila cell lines revealed a close correlation between the gene-expression programs controlled by MED13 and MED12, suggesting their concerted actions in gene regulation (7,8).Drosophila provides a powerful model system for the genetic analysis of obesity (9-11). The processes that regulate energy homeostasis, such as energy storage and mobilization of fat in adipose tissue of the fat bo...

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“…The dmef2-GAL4 driver line is described in ref. 61 and was obtained from R. Ordway (Pennsylvania State University, University Park, PA).…”

Section: Methodsmentioning

confidence: 99%

The PINK1/Parkin pathway regulates mitochondrial morphology

Poole

Thomas

Andrews

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

787

674

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Loss-of-function mutations in the PTEN-induced kinase 1 (PINK1) or parkin genes, which encode a mitochondrially localized serine/ threonine kinase and a ubiquitin-protein ligase, respectively, result in recessive familial forms of Parkinsonism. Genetic studies in Drosophila indicate that PINK1 acts upstream of Parkin in a common pathway that influences mitochondrial integrity in a subset of tissues, including flight muscle and dopaminergic neurons. The mechanism by which PINK1 and Parkin influence mitochondrial integrity is currently unknown, although mutations in the PINK1 and parkin genes result in enlarged or swollen mitochondria, suggesting a possible regulatory role for the PINK1/Parkin pathway in mitochondrial morphology. To address this hypothesis, we examined the influence of genetic alterations affecting the machinery that governs mitochondrial morphology on the PINK1 and parkin mutant phenotypes. We report that heterozygous loss-offunction mutations of drp1, which encodes a key mitochondrial fission-promoting component, are largely lethal in a PINK1 or parkin mutant background. Conversely, the flight muscle degeneration and mitochondrial morphological alterations that result from mutations in PINK1 and parkin are strongly suppressed by increased drp1 gene dosage and by heterozygous loss-of-function mutations affecting the mitochondrial fusion-promoting factors OPA1 and Mfn2. Finally, we find that an eye phenotype associated with increased PINK1/Parkin pathway activity is suppressed by perturbations that reduce mitochondrial fission and enhanced by perturbations that reduce mitochondrial fusion. Our studies suggest that the PINK1/Parkin pathway promotes mitochondrial fission and that the loss of mitochondrial and tissue integrity in PINK1 and parkin mutants derives from reduced mitochondrial fission.caused by the degeneration of dopaminergic neurons in the midbrain. The molecular mechanisms underlying neurodegeneration in PD remain unclear, although substantial evidence suggests that mitochondrial dysfunction is a major contributor: Several mitochondrial toxins induce PD-like symptoms in humans and animal models (1, 2); systemic mitochondrial dysfunction appears to be a feature of a large proportion of PD sufferers (3); and several genes involved in rare heritable forms of Parkinsonism have been implicated in mitochondrial biology, including the PTEN-induced kinase 1 (PINK1) and parkin genes (4, 5).The PINK1 and parkin genes encode a mitochondrially localized serine/threonine kinase and an E3 ubiquitin-protein ligase, respectively (6-13). Although a number of substrates of PINK1 and Parkin have been described, these advances have led to dramatically varying models of pathogenesis (5,(14)(15)(16)(17)(18)(19), making it unclear precisely how PINK1 and Parkin influence neuronal integrity. Genetic studies of highly conserved Drosophila orthologs of parkin and PINK1 indicate that PINK1 acts upstream of Parkin in a common pathway that influences the integrity of flight muscle, sperm, and a subset of dopaminer...

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Wingless Signaling InducesnautilusExpression in the Ventral Mesoderm of theDrosophilaEmbryo

Cited by 210 publications

References 0 publications

A Novel MitoTimer Reporter Gene for Mitochondrial Content, Structure, Stress, and Damage in Vivo

A Novel MitoTimer Reporter Gene for Mitochondrial Content, Structure, Stress, and Damage in Vivo

Heart- and muscle-derived signaling system dependent on MED13 and Wingless controls obesity in Drosophila

The PINK1/Parkin pathway regulates mitochondrial morphology

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