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14 pages, 3281 KiB

Open AccessArticle

In-Depth Annotation of the Drosophila Bithorax-Complex Reveals the Presence of Several Alternative ORFs That Could Encode for Motif-Rich Peptides

by Magali Naville and Samir Merabet

Cells 2021, 10(11), 2983; https://doi.org/10.3390/cells10112983 - 02 Nov 2021

Viewed by 2099

Abstract

It is recognized that a large proportion of eukaryotic RNAs and proteins is not produced from conventional genes but from short and alternative (alt) open reading frames (ORFs) that are not captured by gene prediction programs. Here we present an in silico prediction [...] Read more.

It is recognized that a large proportion of eukaryotic RNAs and proteins is not produced from conventional genes but from short and alternative (alt) open reading frames (ORFs) that are not captured by gene prediction programs. Here we present an in silico prediction of altORFs by applying several selecting filters based on evolutionary conservation and annotations of previously characterized altORF peptides. Our work was performed in the Bithorax-complex (BX-C), which was one of the first genomic regions described to contain long non-coding RNAs in Drosophila. We showed that several altORFs could be predicted from coding and non-coding sequences of BX-C. In addition, the selected altORFs encode for proteins that contain several interesting molecular features, such as the presence of transmembrane helices or a general propensity to be rich in short interaction motifs. Of particular interest, one altORF encodes for a protein that contains a peptide sequence found in specific isoforms of two Drosophila Hox proteins. Our work thus suggests that several altORF proteins could be produced from a particular genomic region known for its critical role during Drosophila embryonic development. The molecular signatures of these altORF proteins further suggests that several of them could make numerous protein–protein interactions and be of functional importance in vivo. Full article

(This article belongs to the Special Issue Drosophila: A Model for Genetic Research)

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14 pages, 3288 KiB

Open AccessArticle

Chemical Genetic Screen in Drosophila Germline Uncovers Small Molecule Drugs That Sensitize Stem Cells to Insult-Induced Apoptosis

by Julien Roy Ishibashi, Riya Keshri, Tommy Henry Taslim, Daniel Kennedy Brewer, Tung Ching Chan, Scott Lyons, Anika Marie McManamen, Ashley Chen, Debra Del Castillo and Hannele Ruohola-Baker

Cells 2021, 10(10), 2771; https://doi.org/10.3390/cells10102771 - 16 Oct 2021

Cited by 2 | Viewed by 2630

Abstract

Cancer stem cells, in contrast to their more differentiated daughter cells, can endure genotoxic insults, escape apoptosis, and cause tumor recurrence. Understanding how normal adult stem cells survive and go to quiescence may help identify druggable pathways that cancer stem cells have co-opted. [...] Read more.

Cancer stem cells, in contrast to their more differentiated daughter cells, can endure genotoxic insults, escape apoptosis, and cause tumor recurrence. Understanding how normal adult stem cells survive and go to quiescence may help identify druggable pathways that cancer stem cells have co-opted. In this study, we utilize a genetically tractable model for stem cell survival in the Drosophila gonad to screen drug candidates and probe chemical-genetic interactions. Our study employs three levels of small molecule screening: (1) a medium-throughput primary screen in male germline stem cells (GSCs), (2) a secondary screen with irradiation and protein-constrained food in female GSCs, and (3) a tertiary screen in breast cancer organoids in vitro. Herein, we uncover a series of small molecule drug candidates that may sensitize cancer stem cells to apoptosis. Further, we have assessed these small molecules for chemical-genetic interactions in the germline and identified the NF-κB pathway as an essential and druggable pathway in GSC quiescence and viability. Our study demonstrates the power of the Drosophila stem cell niche as a model system for targeted drug discovery. Full article

(This article belongs to the Special Issue Drosophila: A Model for Genetic Research)

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31 pages, 9939 KiB

Open AccessArticle

A Candidate RNAi Screen Reveals Diverse RNA-Binding Protein Phenotypes in Drosophila Flight Muscle

by Shao-Yen Kao, Elena Nikonova, Sabrina Chaabane, Albiona Sabani, Alexandra Martitz, Anja Wittner, Jakob Heemken, Tobias Straub and Maria L. Spletter

Cells 2021, 10(10), 2505; https://doi.org/10.3390/cells10102505 - 22 Sep 2021

Cited by 4 | Viewed by 3520

Abstract

The proper regulation of RNA processing is critical for muscle development and the fine-tuning of contractile ability among muscle fiber-types. RNA binding proteins (RBPs) regulate the diverse steps in RNA processing, including alternative splicing, which generates fiber-type specific isoforms of structural proteins that [...] Read more.

The proper regulation of RNA processing is critical for muscle development and the fine-tuning of contractile ability among muscle fiber-types. RNA binding proteins (RBPs) regulate the diverse steps in RNA processing, including alternative splicing, which generates fiber-type specific isoforms of structural proteins that confer contractile sarcomeres with distinct biomechanical properties. Alternative splicing is disrupted in muscle diseases such as myotonic dystrophy and dilated cardiomyopathy and is altered after intense exercise as well as with aging. It is therefore important to understand splicing and RBP function, but currently, only a small fraction of the hundreds of annotated RBPs expressed in muscle have been characterized. Here, we demonstrate the utility of Drosophila as a genetic model system to investigate basic developmental mechanisms of RBP function in myogenesis. We find that RBPs exhibit dynamic temporal and fiber-type specific expression patterns in mRNA-Seq data and display muscle-specific phenotypes. We performed knockdown with 105 RNAi hairpins targeting 35 RBPs and report associated lethality, flight, myofiber and sarcomere defects, including flight muscle phenotypes for Doa, Rm62, mub, mbl, sbr, and clu. Knockdown phenotypes of spliceosome components, as highlighted by phenotypes for A-complex components SF1 and Hrb87F (hnRNPA1), revealed level- and temporal-dependent myofibril defects. We further show that splicing mediated by SF1 and Hrb87F is necessary for Z-disc stability and proper myofibril development, and strong knockdown of either gene results in impaired localization of kettin to the Z-disc. Our results expand the number of RBPs with a described phenotype in muscle and underscore the diversity in myofibril and transcriptomic phenotypes associated with splicing defects. Drosophila is thus a powerful model to gain disease-relevant insight into cellular and molecular phenotypes observed when expression levels of splicing factors, spliceosome components and splicing dynamics are altered. Full article

(This article belongs to the Special Issue Drosophila: A Model for Genetic Research)

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15 pages, 3148 KiB

Open AccessArticle

The RNA-Binding Protein SBR (Dm NXF1) Is Required for the Constitution of Medulla Boundaries in Drosophila melanogaster Optic Lobes

by Ludmila Mamon, Anna Yakimova, Daria Kopytova and Elena Golubkova

Cells 2021, 10(5), 1144; https://doi.org/10.3390/cells10051144 - 10 May 2021

Cited by 1 | Viewed by 3183

Abstract

Drosophila melanogaster sbr (small bristles) is an orthologue of the Nxf1 (nuclear export factor 1) genes in different Opisthokonta. The known function of Nxf1 genes is the export of various mRNAs from the nucleus to the cytoplasm. The cytoplasmic [...] Read more.

Drosophila melanogaster sbr (small bristles) is an orthologue of the Nxf1 (nuclear export factor 1) genes in different Opisthokonta. The known function of Nxf1 genes is the export of various mRNAs from the nucleus to the cytoplasm. The cytoplasmic localization of the SBR protein indicates that the nuclear export function is not the only function of this gene in Drosophila. RNA-binding protein SBR enriches the nucleus and cytoplasm of specific neurons and glial cells. In sbr¹² mutant males, the disturbance of medulla boundaries correlates with the defects of photoreceptor axons pathfinding, axon bundle individualization, and developmental neurodegeneration. RNA-binding protein SBR participates in processes allowing axons to reach and identify their targets. Full article

(This article belongs to the Special Issue Drosophila: A Model for Genetic Research)

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Review

Jump to: Research

13 pages, 1269 KiB

Open AccessFeature PaperReview

Drosophila Heart as a Model for Cardiac Development and Diseases

by Anissa Souidi and Krzysztof Jagla

Cells 2021, 10(11), 3078; https://doi.org/10.3390/cells10113078 - 08 Nov 2021

Cited by 19 | Viewed by 4930

Abstract

The Drosophila heart, also referred to as the dorsal vessel, pumps the insect blood, the hemolymph. The bilateral heart primordia develop from the most dorsally located mesodermal cells, migrate coordinately, and fuse to form the cardiac tube. Though much simpler, the fruit fly [...] Read more.

The Drosophila heart, also referred to as the dorsal vessel, pumps the insect blood, the hemolymph. The bilateral heart primordia develop from the most dorsally located mesodermal cells, migrate coordinately, and fuse to form the cardiac tube. Though much simpler, the fruit fly heart displays several developmental and functional similarities to the vertebrate heart and, as we discuss here, represents an attractive model system for dissecting mechanisms of cardiac aging and heart failure and identifying genes causing congenital heart diseases. Fast imaging technologies allow for the characterization of heartbeat parameters in the adult fly and there is growing evidence that cardiac dysfunction in human diseases could be reproduced and analyzed in Drosophila, as discussed here for heart defects associated with the myotonic dystrophy type 1. Overall, the power of genetics and unsuspected conservation of genes and pathways puts Drosophila at the heart of fundamental and applied cardiac research. Full article

(This article belongs to the Special Issue Drosophila: A Model for Genetic Research)

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22 pages, 422 KiB

Open AccessReview

Drosophila Accessory Gland: A Complementary In Vivo Model to Bring New Insight to Prostate Cancer

by Amandine Rambur, Marine Vialat, Claude Beaudoin, Corinne Lours-Calet, Jean-Marc Lobaccaro, Silvère Baron, Laurent Morel and Cyrille de Joussineau

Cells 2021, 10(9), 2387; https://doi.org/10.3390/cells10092387 - 10 Sep 2021

Cited by 2 | Viewed by 2687

Abstract

Prostate cancer is the most common cancer in aging men. Despite recent progress, there are still few effective treatments to cure its aggressive and metastatic stages. A better understanding of the molecular mechanisms driving disease initiation and progression appears essential to support the [...] Read more.

Prostate cancer is the most common cancer in aging men. Despite recent progress, there are still few effective treatments to cure its aggressive and metastatic stages. A better understanding of the molecular mechanisms driving disease initiation and progression appears essential to support the development of more efficient therapies and improve patient care. To do so, multiple research models, such as cell culture and mouse models, have been developed over the years and have improved our comprehension of the biology of the disease. Recently, a new model has been added with the use of the Drosophila accessory gland. With a high level of conservation of major signaling pathways implicated in human disease, this functional equivalent of the prostate represents a powerful, inexpensive, and rapid in vivo model to study epithelial carcinogenesis. The purpose of this review is to quickly overview the existing prostate cancer models, including their strengths and limitations. In particular, we discuss how the Drosophila accessory gland can be integrated as a convenient complementary model by bringing new understanding in the mechanisms driving prostate epithelial tumorigenesis, from initiation to metastatic formation. Full article

(This article belongs to the Special Issue Drosophila: A Model for Genetic Research)

12 pages, 1414 KiB

Open AccessReview

Impact of Microorganisms and Parasites on Neuronally Controlled Drosophila Behaviours

by Martina Montanari and Julien Royet

Cells 2021, 10(9), 2350; https://doi.org/10.3390/cells10092350 - 08 Sep 2021

Cited by 8 | Viewed by 3306

Abstract

Like all invertebrates, flies such as Drosophila lack an adaptive immune system and depend on their innate immune system to protect them against pathogenic microorganisms and parasites. In recent years, it appears that the nervous systems of eucaryotes not only control animal behavior [...] Read more.

Like all invertebrates, flies such as Drosophila lack an adaptive immune system and depend on their innate immune system to protect them against pathogenic microorganisms and parasites. In recent years, it appears that the nervous systems of eucaryotes not only control animal behavior but also cooperate and synergize very strongly with the animals’ immune systems to detect and fight potential pathogenic threats, and allow them to adapt their behavior to the presence of microorganisms and parasites that coexist with them. This review puts into perspective the latest progress made using the Drosophila model system, in this field of research, which remains in its infancy. Full article

(This article belongs to the Special Issue Drosophila: A Model for Genetic Research)

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15 pages, 1328 KiB

Open AccessReview

Ion Channels in Epithelial Dynamics and Morphogenesis

by Ankit Roy Choudhury, Jörg Großhans and Deqing Kong

Cells 2021, 10(9), 2280; https://doi.org/10.3390/cells10092280 - 01 Sep 2021

Cited by 5 | Viewed by 4518

Abstract

Mechanosensitive ion channels mediate the neuronal sensation of mechanical signals such as sound, touch, and pain. Recent studies point to a function of these channel proteins in cell types and tissues in addition to the nervous system, such as epithelia, where they have [...] Read more.

Mechanosensitive ion channels mediate the neuronal sensation of mechanical signals such as sound, touch, and pain. Recent studies point to a function of these channel proteins in cell types and tissues in addition to the nervous system, such as epithelia, where they have been little studied, and their role has remained elusive. Dynamic epithelia are intrinsically exposed to mechanical forces. A response to pull and push is assumed to constitute an essential part of morphogenetic movements of epithelial tissues, for example. Mechano-gated channels may participate in sensing and responding to such forces. In this review, focusing on Drosophila, we highlight recent results that will guide further investigations concerned with the mechanistic role of these ion channels in epithelial cells. Full article

(This article belongs to the Special Issue Drosophila: A Model for Genetic Research)

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12 pages, 1317 KiB

Open AccessReview

Drosophila, an Integrative Model to Study the Features of Muscle Stem Cells in Development and Regeneration

by Hadi Boukhatmi

Cells 2021, 10(8), 2112; https://doi.org/10.3390/cells10082112 - 17 Aug 2021

Cited by 5 | Viewed by 4566

Abstract

Muscle stem cells (MuSCs) are essential for muscle growth, maintenance and repair. Over the past decade, experiments in Drosophila have been instrumental in understanding the molecular and cellular mechanisms regulating MuSCs (also known as adult muscle precursors, AMPs) during development. A large number [...] Read more.

Muscle stem cells (MuSCs) are essential for muscle growth, maintenance and repair. Over the past decade, experiments in Drosophila have been instrumental in understanding the molecular and cellular mechanisms regulating MuSCs (also known as adult muscle precursors, AMPs) during development. A large number of genetic tools available in fruit flies provides an ideal framework to address new questions which could not be addressed with other model organisms. This review reports the main findings revealed by the study of Drosophila AMPs, with a specific focus on how AMPs are specified and properly positioned, how they acquire their identity and which are the environmental cues controlling their behavior and fate. The review also describes the recent identification of the Drosophila adult MuSCs that have similar characteristics to vertebrates MuSCs. Integration of the different levels of MuSCs analysis in flies is likely to provide new fundamental knowledge in muscle stem cell biology largely applicable to other systems. Full article

(This article belongs to the Special Issue Drosophila: A Model for Genetic Research)

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22 pages, 4616 KiB

Open AccessFeature PaperReview

Drosophila Models Rediscovered with Super-Resolution Microscopy

by Szilárd Szikora, Péter Görög, Csaba Kozma and József Mihály

Cells 2021, 10(8), 1924; https://doi.org/10.3390/cells10081924 - 29 Jul 2021

Cited by 2 | Viewed by 3146

Abstract

With the advent of super-resolution microscopy, we gained a powerful toolbox to bridge the gap between the cellular- and molecular-level analysis of living organisms. Although nanoscopy is broadly applicable, classical model organisms, such as fruit flies, worms and mice, remained the leading subjects [...] Read more.

With the advent of super-resolution microscopy, we gained a powerful toolbox to bridge the gap between the cellular- and molecular-level analysis of living organisms. Although nanoscopy is broadly applicable, classical model organisms, such as fruit flies, worms and mice, remained the leading subjects because combining the strength of sophisticated genetics, biochemistry and electrophysiology with the unparalleled resolution provided by super-resolution imaging appears as one of the most efficient approaches to understanding the basic cell biological questions and the molecular complexity of life. Here, we summarize the major nanoscopic techniques and illustrate how these approaches were used in Drosophila model systems to revisit a series of well-known cell biological phenomena. These investigations clearly demonstrate that instead of simply achieving an improvement in image quality, nanoscopy goes far beyond with its immense potential to discover novel structural and mechanistic aspects. With the examples of synaptic active zones, centrosomes and sarcomeres, we will explain the instrumental role of super-resolution imaging pioneered in Drosophila in understanding fundamental subcellular constituents. Full article

(This article belongs to the Special Issue Drosophila: A Model for Genetic Research)

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