Drosophila Heart as a Model for Cardiac Development and Diseases

Souidi, Anissa; Jagla, Krzysztof

doi:10.3390/cells10113078

Cited by 35 publications

(29 citation statements)

References 92 publications

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“…However, the underlying mechanisms remain poorly understood, impeding the development of adapted treatments. As we previously demonstrated (Auxerre-Plantié et al, 2019;Souidi et al, 2018;Souidi and Jagla, 2021), Drosophila DM1 models recapitulate all the cardiac phenotypes observed in DM1 patients and so could help gain insight into gene deregulations underlying DM1-associated DCM.…”

Section: Discussionmentioning

confidence: 75%

Deregulations of miR-1 and its target Multiplexin promote dilated cardiomyopathy associated with myotonic dystrophy type 1

Souidi

Nakamori

Zmojdzian

et al. 2022

Preprint

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Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy. It is caused by the excessive expansion of non-coding CTG repeat, which when transcribed affect functions of RNA-binding factors. Specifically, MBNL1 is sequestered in nuclear foci while CELF1 is stabilised, with adverse effects on alternative splicing, processing and stability of a large set of muscular and cardiac transcripts. Among these effects, inefficient processing and down-regulation of muscle- and heart-specific miRNA, miR-1, has been reported in DM1 patients, but the impact of reduced miR-1 on DM1 pathogenesis was unknown. Here, we used Drosophila DM1 models to explore miR-1 involvement in cardiac dysfunction in DM1. We found that miR-1 down-regulation in the heart led to dilated cardiomyopathy (DCM), a DM1-associated phenotype. We then combined in silico screening for miR-1 targets with transcriptional profiling of DM1 cardiac cells to identify miR-1 target genes with potential roles in DCM. We identified Multiplexin (Mp) as a new cardiac miR-1 target involved in DM1. Mp and its human ortholog Col15A1 were both highly enriched in cardiac cells of DCM-developing DM1 flies and in heart samples from DM1 patients with DCM, respectively. Importantly, when overexpressed in the heart, Mp induced DCM, whereas its attenuation ameliorated the DCM phenotype in aged DM1 flies. Reduced levels of miR-1 and consecutive up-regulation of its target Mp/Col15A1 are thus critical in DM1-associated DCM.

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Section: Discussionmentioning

confidence: 75%

Deregulations of miR-1 and its target Multiplexin promote dilated cardiomyopathy associated with myotonic dystrophy type 1

Souidi

Nakamori

Zmojdzian

et al. 2022

Preprint

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“…During recent decades, Drosophila melanogaster has become a standard model for the investigation of genetic and biochemical aetiologies of clinically relevant diseases [ 24 ]. TMEM43 is evolutionarily highly conserved, and CG8111 is the homologous protein present in the fruit fly.…”

Section: Discussionmentioning

confidence: 99%

A Drosophila melanogaster model for TMEM43-related arrhythmogenic right ventricular cardiomyopathy type 5

Klinke

Meyer

Ratnavadivel

et al. 2022

Cell. Mol. Life Sci.

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Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a severe cardiac disease that leads to heart failure or sudden cardiac death (SCD). For the pathogenesis of ARVC, various mutations in at least eight different genes have been identified. A rare form of ARVC is associated with the mutation TMEM43 p.S358L, which is a fully penetrant variant in male carriers. TMEM43 p.S358 is homologous to CG8111 p.S333 in Drosophila melanogaster. We established CRISPR/Cas9-mediated CG8111 knock-out mutants in Drosophila, as well as transgenic fly lines carrying an overexpression construct of the CG8111 p.S333L substitution. Knock-out flies developed normally, whereas the overexpression of CG8111 p.S333L caused growth defects, loss of body weight, cardiac arrhythmias, and premature death. An evaluation of a series of model mutants that replaced S333 by selected amino acids proved that the conserved serine is critical for the physiological function of CG8111. Metabolomic and proteomic analyses revealed that the S333 in CG8111 is essential to proper energy homeostasis and lipid metabolism in the fly. Of note, metabolic impairments were also found in the murine Tmem43 disease model, and fibrofatty replacement is a hallmark of human ARVC5. These findings contribute to a more comprehensive understanding of the molecular functions of CG8111 in Drosophila, and can represent a valuable basis to assess the aetiology of the human TMEM43 p.S358L variant in more detail.

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“…Several key characteristics related to cellular processes, signalling pathways and gene conservation endorse D. melanogaster as a model of choice for studying human cardiac development, function and diseases. First, although seemingly simplistic, the fruit fly circulatory system, consisting of a tube-like heart that pumps the haemolymph, shows developmental and functional similarities to the vertebrate heart [134][135][136][137]. Second, both organisms (D. melanogaster and H. sapiens) share some regulatory cardiogenic networks encompassing critical cardiac transcription factors such as tin/Nkx2.5, Mef2/Mef2C, pannier/GATA family and Hand/HAND1 and HAND2, which are required for cardiac progenitor specification [137][138][139][140][141][142][143].…”

Section: Cardiac Disordersmentioning

confidence: 99%

“…First, although seemingly simplistic, the fruit fly circulatory system, consisting of a tube-like heart that pumps the haemolymph, shows developmental and functional similarities to the vertebrate heart [134][135][136][137]. Second, both organisms (D. melanogaster and H. sapiens) share some regulatory cardiogenic networks encompassing critical cardiac transcription factors such as tin/Nkx2.5, Mef2/Mef2C, pannier/GATA family and Hand/HAND1 and HAND2, which are required for cardiac progenitor specification [137][138][139][140][141][142][143]. Third, there is a strong gene conservation with human genes, particularly with disease-related genes [144].…”

Section: Cardiac Disordersmentioning

confidence: 99%

Inter-Species Rescue of Mutant Phenotype—The Standard for Genetic Analysis of Human Genetic Disorders in Drosophila melanogaster Model

Ecovoiu

Rațiu

Micheu

et al. 2022

IJMS

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Drosophila melanogaster (the fruit fly) is arguably a superstar of genetics, an astonishing versatile experimental model which fueled no less than six Nobel prizes in medicine. Nowadays, an evolving research endeavor is to simulate and investigate human genetic diseases in the powerful D. melanogaster platform. Such a translational experimental strategy is expected to allow scientists not only to understand the molecular mechanisms of the respective disorders but also to alleviate or even cure them. In this regard, functional gene orthology should be initially confirmed in vivo by transferring human or vertebrate orthologous transgenes in specific mutant backgrounds of D. melanogaster. If such a transgene rescues, at least partially, the mutant phenotype, then it qualifies as a strong candidate for modeling the respective genetic disorder in the fruit fly. Herein, we review various examples of inter-species rescue of relevant mutant phenotypes of the fruit fly and discuss how these results recommend several human genes as candidates to study and validate genetic variants associated with human diseases. We also consider that a wider implementation of this evolutionist exploratory approach as a standard for the medicine of genetic disorders would allow this particular field of human health to advance at a faster pace.

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Drosophila Heart as a Model for Cardiac Development and Diseases

Cited by 35 publications

References 92 publications

Deregulations of miR-1 and its target Multiplexin promote dilated cardiomyopathy associated with myotonic dystrophy type 1

Deregulations of miR-1 and its target Multiplexin promote dilated cardiomyopathy associated with myotonic dystrophy type 1

A Drosophila melanogaster model for TMEM43-related arrhythmogenic right ventricular cardiomyopathy type 5

Inter-Species Rescue of Mutant Phenotype—The Standard for Genetic Analysis of Human Genetic Disorders in Drosophila melanogaster Model

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