The Conserved ADAMTS-like Protein Lonely heart Mediates Matrix Formation and Cardiac Tissue Integrity

Drechsler, Maik; Schmidt, Ariane C.; Meyer, Heiko; Paululat, Achim

doi:10.1371/journal.pgen.1003616

Cited by 51 publications

(90 citation statements)

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“…4E). This phenotype is strikingly similar to other cardiac extracellular-matrix mutants, such as Lonely heart (loh) (Drechsler et al, 2013). To determine whether pericardial cells detached in the context of abnormal extracellular-matrix formation, we stained the flies for pericardin, a type IV collagen that is crucial for maintaining cardiac integrity in Drosophila.…”

Section: Misexpression Of Nedd4 Disrupts the Patterning Of Cardioblassupporting

confidence: 53%

The E3 ubiquitin ligase Nedd4/Nedd4L is directly regulated by microRNA 1

et al. 2017

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miR-1 is a small noncoding RNA molecule that modulates gene expression in heart and skeletal muscle. Loss of Drosophila miR-1 produces defects in somatic muscle and embryonic heart development, which have been partly attributed to miR-1 directly targeting Delta to decrease Notch signaling. Here, we show that overexpression of miR-1 in the fly wing can paradoxically increase Notch activity independently of its effects on Delta. Analyses of potential miR-1 targets revealed that miR-1 directly regulates the 3′UTR of the E3 ubiquitin ligase Nedd4. Analysis of embryonic and adult fly heart revealed that the Nedd4 protein regulates heart development in Drosophila. Larval fly hearts overexpressing miR-1 have profound defects in actin filament organization that are partially rescued by concurrent overexpression of Nedd4. These results indicate that miR-1 and Nedd4 act together in the formation and actindependent patterning of the fly heart. Importantly, we have found that the biochemical and genetic relationship between miR-1 and the mammalian ortholog Nedd4-like (Nedd4l) is evolutionarily conserved in the mammalian heart, potentially indicating a role for Nedd4L in mammalian postnatal maturation. Thus, miR-1-mediated regulation of Nedd4/Nedd4L expression may serve to broadly modulate the trafficking or degradation of Nedd4/Nedd4L substrates in the heart.

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Section: Misexpression Of Nedd4 Disrupts the Patterning Of Cardioblassupporting

confidence: 53%

The E3 ubiquitin ligase Nedd4/Nedd4L is directly regulated by microRNA 1

et al. 2017

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“…Fibrosis can be visualized in whole-mount hearts using confocal microscopy with actin-phalloidin staining or immunohistochemistry for extracellular matrix proteins such as collagens (especially pericardin), perlecan and the ADAMTS (a disintegrin and metalloprotease with thrombospondin repeats) homolog Lonely heart (Chartier et al, 2002;Drechsler et al, 2013). Stimulation-induced heart failure can also be measured in whole flies using external electrical pacing (Wessells et al, 2004).…”

Section: The Heartmentioning

confidence: 99%

Drosophilaas a model to study obesity and metabolic disease

Musselman

Kühnlein

2018

Journal of Experimental Biology

176

130

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Excess adipose fat accumulation, or obesity, is a growing problem worldwide in terms of both the rate of incidence and the severity of obesity-associated metabolic disease. Adipose tissue evolved in animals as a specialized dynamic lipid storage depot: adipose cells synthesize fat (a process called lipogenesis) when energy is plentiful and mobilize stored fat (a process called lipolysis) when energy is needed. When a disruption of lipid homeostasis favors increased fat synthesis and storage with little turnover owing to genetic predisposition, overnutrition or sedentary living, complications such as diabetes and cardiovascular disease are more likely to arise. The vinegar fly Drosophila melanogaster (Diptera: Drosophilidae) is used as a model to better understand the mechanisms governing fat metabolism and distribution. Flies offer a wealth of paradigms with which to study the regulation and physiological effects of fat accumulation. Obese flies accumulate triacylglycerols in the fat body, an organ similar to mammalian adipose tissue, which specializes in lipid storage and catabolism. Discoveries in Drosophila have ranged from endocrine hormones that control obesity to subcellular mechanisms that regulate lipogenesis and lipolysis, many of which are evolutionarily conserved. Furthermore, obese flies exhibit pathophysiological complications, including hyperglycemia, reduced longevity and cardiovascular functionsimilar to those observed in obese humans. Here, we review some of the salient features of the fly that enable researchers to study the contributions of feeding, absorption, distribution and the metabolism of lipids to systemic physiology.

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“…Nevertheless, flies with certain genetic defects in cardiac development and function suffer from reduced fitness and longevity (e.g. Drechsler et al, 2013;Ocorr et al, 2007). However, specific manipulations of the cardiac ECM may increase longevity (Sessions et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…The reason for this restriction is the fact that during diastole we observed backflow of particles from the aorta into the posterior heart chamber, which we consider artificial and caused by the preparation procedure (see Movie 2C). Visualising haemolymph streaming in intact specimens showed that in larvae and prepupae haemolymph streaming is unidirectional (Choma et al, 2011;Drechsler et al, 2013). This indicates that unidirectional haemolymph flow inside the heart tube is affected by the dissection procedure, presumably due to an impaired connection of the heart tube to the alary muscles.…”

Section: Intracardiac Valve Cells -Mode Of Operationmentioning

confidence: 99%

“…To address this issue, we are currently working on optimising particle injection into living mutant animals, with the aim of reliably visualising haemolymph streaming inside the heart. Several methods have been applied to analyse pumping activity of the heart in adult Drosophila (Choma et al, 2010), prepupal Drosophila (Drechsler et al, 2013) and adult Anopheles (Glenn et al, 2010), but these methods lack the possibility of tracking individual particle movements inside the heart lumen. It will thus be interesting to analyse how mutant valve cells modulate hydrodynamic parameters, such as velocity and directionality of haemolymph flow, in vivo.…”

Section: Differentiation Of the Intracardiac Valvementioning

confidence: 99%

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Formation and function of intracardiac valve cells in the Drosophila heart

Lammers

Abeln

Hüsken

et al. 2017

Journal of Experimental Biology

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Drosophila harbours a simple tubular heart that ensures haemolymph circulation within the body. The heart is built by a few different cell types, including cardiomyocytes that define the luminal heart channel and ostia cells that constitute openings in the heart wall allowing haemolymph to enter the heart chamber. Regulation of flow directionality within a tube, such as blood flow in arteries or insect haemolymph within the heart lumen, requires a dedicated gate, valve or flap-like structure that prevents backflow of fluids. In the Drosophila heart, intracardiac valves provide this directionality of haemolymph streaming, with one valve being present in larvae and three valves in the adult fly. Each valve is built by two specialised cardiomyocytes that exhibit a unique histology. We found that the capacity to open and close the heart lumen relies on a unique myofibrillar setting as well as on the presence of large membranous vesicles. These vesicles are of endocytic origin and probably represent unique organelles of valve cells. Moreover, we characterised the working mode of the cells in real time. Valve cells exhibit a highly flexible shape and, during each heartbeat, oscillating shape changes result in closing and opening of the heart channel. Finally, we identified a set of novel valve cell markers useful for future in-depth analyses of cell differentiation in wild-type and mutant animals.

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The Conserved ADAMTS-like Protein Lonely heart Mediates Matrix Formation and Cardiac Tissue Integrity

Cited by 51 publications

References 50 publications

The E3 ubiquitin ligase Nedd4/Nedd4L is directly regulated by microRNA 1

The E3 ubiquitin ligase Nedd4/Nedd4L is directly regulated by microRNA 1

Drosophilaas a model to study obesity and metabolic disease

Formation and function of intracardiac valve cells in the Drosophila heart

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