Drosophila: a "model" model system to study neurodegeneration

The fruit fly, Drosophila melanogaster, is a powerful model genetic organism that has been used since the turn of the previous century in the study of complex biological problems. In the last decade, numerous researchers have focused their attention on understanding neurodegenerative diseases by utilizing this model system. Numerous Drosophila mutants have been isolated that profoundly affect neural viability and integrity of the nervous system with age. Additionally, many transgenic strains have been developed as models of human disease conditions. We review the existing Drosophila neurodegenerative mutants and transgenic disease models, and discuss the role of the fruit fly in therapeutic development for neurodegenerative diseases.     

Insect transgenesis and its potential role in agriculture and human health

The ability to genetically engineer insects other than Drosophila melanogaster has further extended modern genetic techniques into important insect pest species ranging from fruit fly pests of horticulture to mosquito vectors of human disease. In only a relatively short period of time, a range of transgenes have been inserted into more than 10 insect pest species. Genetic transformation of these pest species has proven to be a very important laboratory tool in analyzing gene function and effects on phenotype however the full extension of this technology into the field is yet to be realized. Here we briefly review the development of transgenic technology in pest insect species and discuss the challenges that remain in this applied area of insect genetics and entomology.     

Of flies and men; p53, a tumour suppressor

The completion of the Drosophila genome sequencing project [Science 287 (2000) 2185] has reconfirmed the fruit fly as a model organism to study human disease. Comparison studies have shown that two thirds of genes implicated in human cancers have counterparts in the fly [Curr. Opin. Genet. Dev. 11 (2001) 274; J. Cell Biol. 150 (2000) F23], including the tumour suppressor, p53. The suitability of the fruit fly to study the function of the tumour suppressor p53 is further exemplified by the lack of p53 family members within the fly genome, i.e., no homologues to p63 and p73 have been identified. Hence, there is no redundancy between family members greatly facilitating the analysis of p53 function. In addition, studying p53 in Drosophila provides an opportunity to learn about the evolution of tumour suppressors. Here, we will discuss what is known about Drosophila p53 in relation to human p53.     

果蝇在肿瘤学研究中的优势及应用前景

果蝇作为研究人类疾病的模式生物, 与哺乳动物不仅在基本的生物学、生理学和神经系统机能等方面比较相似, 而且果蝇有其作为模式生物的独特优势。近年来的研究表明, 果蝇和人类在肿瘤发生信号通路等方面的保守性很高, 而且果蝇具有很强的遗传学可操作性, 是肿瘤学研究有效的模型之一, 可用于研究人类肿瘤发生、发展、转移等分子机制。文章综述了果蝇在肿瘤学研究中的优势、已建立的用于研究特定癌症的果蝇模型, 并对其在未来肿瘤学的研究方向进行展望, 以期为国内肿瘤学研究和抗肿瘤药物的研发提供参考。     

Connecting cell-cycle activation to neurodegeneration in Drosophila

Studies in cell-culture systems and in postmortem tissue from human disease have suggested a connection between cell-cycle activation and neurodegeneration. The fruit fly Drosophila melanogaster has recently emerged as a powerful model system in which to model neurodegenerative diseases. Here we review work in the fly that has begun to address some of the important questions regarding the relationship between cell-cycle activation and neurodegeneration in vivo, including recent data implicating cell-cycle activation as a downstream effector of tau-induced neurodegeneration. We suggest how powerful research tools in Drosophila might be utilized to approach fundamental questions that remain.     

The eye of Drosophila as a model system for studying intracellular signaling in ontogenesis and pathogenesis

Many human diseases are caused by malfunction of basic types of cellular activity such as proliferation, differentiation, apoptosis, cell polarization, and migration. In turn, these processes are associated with different routes of intracellular signal transduction. A number of model systems have been designed to study normal and abnormal cellular and molecular processes associated with pathogenesis. The developing eye of the fruit fly Drosophila melanogaster is one of these systems. The sequential development of compound eyes of this insect makes it possible to model human neurodegenerative diseases and mechanisms of carcinogenesis. In this paper we overview the program of the eye development in Drosophila, with emphasis on intracellular signaling pathways that regulate this complex process. We discuss in detail the roles of the Notch, Hedgehog, TGFβ, Wnt, and receptor tyrosine kinase signaling pathways in Drosophila eye development and human pathology. We also briefly describe the modern methods of experimentation with this model organism to analyze the function of human pathogenic proteins.     

A Drosophila melanogaster cell line (S2) facilitates post-genome functional analysis of receptors and ion channels

The complete sequencing of the genome of the fruit fly Drosophila melanogaster offers the prospect of detailed functional analysis of the extensive gene families in this genetic model organism. Comprehensive functional analysis of family members is facilitated by access to a robust, stable and inducible expression system in a fly cell line. Here we show how the Schneider S2 cell line, derived from the Drosophila embryo, provides such an expression system, with the bonus that radioligand binding studies, second messenger assays, ion imaging, patch-clamp electrophysiology and gene silencing can readily be applied. Drosophila is also ideal for the study of new control strategies for insect pests since the receptors and ion channels that many new animal health drugs and crop protection chemicals target can be expressed in this cell line. In addition, many useful orthologues of human disease genes are emerging from the Drosophila genome and the study of their functions and interactions is another area for postgenome applications of S2 cell lines.     

Exploration of host-pathogen interactions using Listeria monocytogenes and Drosophila melanogaster

The facultative intracellular bacterial pathogen Listeria monocytogenes is capable of replicating within a broad range of host cell types and host species. We report here the establishment of the fruit fly Drosophila melanogaster as a new model host for the exploration of L. monocytogenes pathogenesis and host response to infection. Listeria monocytogenes was capable of establishing lethal infections in adult fruit flies and larvae with extensive bacterial replication occurring before host death. Bacteria were found in the cytosol of insect phagocytic cells, and were capable of directing host cell actin polymerization. Bacterial gene products necessary for intracellular replication and cell-to-cell spread within mammalian cells were similarly found to be required within insect cells, and although previous work has suggested that L. monocytogenes virulence gene expression requires temperatures above 30 degrees C, bacteria within insect cells were found to express virulence determinants at 25 degrees C. Mutant strains of Drosophila that were compromised for innate immune responses demonstrated increased susceptibility to L. monocytogenes infection. These data indicate L. monocytogenes infection of fruit flies shares numerous features of mammalian infection, and thus that Drosophila has the potential to serve as a genetically tractable host system that will facilitate the analysis of host cellular responses to L. monocytogenes infection.     

Drosophila RNAi screening in a postgenomic world

Drosophila melanogaster has a long history as a model organism with several unique features that make it an ideal research tool for the study of the relationship between genotype and phenotype. Importantly fundamental genetic principles as well as key human disease genes have been uncovered through the use of Drosophila. The contribution of the fruit fly to science and medicine continues in the postgenomic era as cell-based Drosophila RNAi screens are a cost-effective and scalable enabling technology that can be used to quantify the contribution of different genes to diverse cellular processes. Drosophila high-throughput screens can also be used as integral part of systems-level approaches to describe the architecture and dynamics of cellular networks.     

Drosophila as an In Vivo Model for Human Neurodegenerative Disease

With the increase in the ageing population, neurodegenerative disease is devastating to families and poses a huge burden on society. The brain and spinal cord are extraordinarily complex: they consist of a highly organized network of neuronal and support cells that communicate in a highly specialized manner. One approach to tackling problems of such complexity is to address the scientific questions in simpler, yet analogous, systems. The fruit fly, Drosophila melanogaster, has been proven tremendously valuable as a model organism, enabling many major discoveries in neuroscientific disease research. The plethora of genetic tools available in Drosophila allows for exquisite targeted manipulation of the genome. Due to its relatively short lifespan, complex questions of brain function can be addressed more rapidly than in other model organisms, such as the mouse. Here we discuss features of the fly as a model for human neurodegenerative disease. There are many distinct fly models for a range of neurodegenerative diseases; we focus on select studies from models of polyglutamine disease and amyotrophic lateral sclerosis that illustrate the type and range of insights that can be gleaned. In discussion of these models, we underscore strengths of the fly in providing understanding into mechanisms and pathways, as a foundation for translational and therapeutic research.     

Costs and benefits of sublethal Drosophila C virus infection

Viruses are major evolutionary drivers of insect immune systems. Much of our knowledge of insect immune responses derives from experimental infections using the fruit fly Drosophila melanogaster. Most experiments, however, employ lethal pathogen doses through septic injury, frequently overwhelming host physiology. While this approach has revealed several immune mechanisms, it is less informative about the fitness costs hosts may experience during infection in the wild. Using both systemic and oral infection routes, we find that even apparently benign, sublethal infections with the horizontally transmitted Drosophila C virus (DCV) can cause significant physiological and behavioural morbidity that is relevant for host fitness. We describe DCV‐induced effects on fly reproductive output, digestive health and locomotor activity, and we find that viral morbidity varies according to the concentration of pathogen inoculum, host genetic background and sex. Notably, sublethal DCV infection resulted in a significant increase in fly reproduction, but this effect depended on host genotype. We discuss the relevance of sublethal morbidity for Drosophila ecology and evolution, and more broadly, we remark on the implications of deleterious and beneficial infections for the evolution of insect immunity.     

Drosophila as a lipotoxicity model organism — more than a promise?

Looking back over the century long research career of the fruit fly, Drosophila melanogaster has frequently been in the scientific spotlight with respect to fundamental discoveries in biology. The last decade witnessed the increasing importance of the fly as a human disease model but studies on energy homeostasis and lipometabolism remain in their infancy. This perspective, addressing readers largely unfamiliar with the Drosophila model system, aims to highlight the starting points for which the fly could be employed to gain a deeper understanding of lipotoxicity and possibly contribute to strategies for the identification of novel drug targets relevant to type 2 diabetes mellitus and the metabolic syndrome.     

High-resolution, in vivo magnetic resonance imaging of Drosophila at 18.8 Tesla

High resolution MRI of live Drosophila was performed at 18.8 Tesla, with a field of view less than 5 mm, and administration of manganese or gadolinium-based contrast agents. This study demonstrates the feasibility of MR methods for imaging the fruit fly Drosophila with an NMR spectrometer, at a resolution relevant for undertaking future studies of the Drosophila brain and other organs. The fruit fly has long been a principal model organism for elucidating biology and disease, but without capabilities like those of MRI. This feasibility marks progress toward the development of new in vivo research approaches in Drosophila without the requirement for light transparency or destructive assays.     

The retinoblastoma tumour suppressor in model organisms--new insights from flies and worms

All forms of life on Earth share a common ancestry. As a consequence, Homo sapiens shares a large number of genes essential for the development and maintenance of multicellular life with "simple" animals, such as the fruit fly Drosophila melanogaster and the nematode worm Caenorhabdites elegans. Indeed, Drosophila and C. elegans have successfully been used to unravel fundamental mechanisms underlying animal development. The sequencing of their genomes has revealed that a surprisingly large proportion of genes relevant for human disease have counterparts in the worm and in the fly. This includes many oncogenes and tumour suppressor genes and provides us with a unique opportunity to exploit the advantages of simple model organisms to further our understanding of the molecular basis of cancer. Recent work on the fly and worm homologs of the Retinoblastoma tumour suppressor (pRb) has uncovered some unexpected pRb functions: Evolutionary conserved pRb complexes participate in cell fate determination, repress germline-specific gene expression and interact with RNA interference pathways. Similar complexes appear to operate in human cells.     

Fruit fly research in China

Served as a model organism over a century, fruit fly has significantly pushed forward the development of global scientific research, including in China. The high similarity in genomic features between fruit fly and human enables this tiny insect to benefit the biomedical studies of human diseases. In the past decades, Chinese biologists have used fruit fly to make numerous achievements on understanding the fundamental questions in many diverse areas of biology. Here, we review some of the recent fruit fly studies in China, and mainly focus on those studies in the fields of stem cell biology, cancer therapy and regeneration medicine, neurological disorders and epigenetics.     

The olfactory circuit of the fruit fly Drosophila melanogaster

The olfactory circuit of the fruit fly Drosophila melanogaster has emerged in recent years as an excellent paradigm for studying the principles and mechanisms of information processing in neuronal circuits. We discuss here the organizational principles of the olfactory circuit that make it an attractive model for experimental manipulations, the lessons that have been learned, and future challenges.     

As time flies by: Investigating cardiac aging in the short-lived Drosophila model

Aging is associated with a decline in heart function across the tissue, cellular, and molecular levels. The risk of cardiovascular disease grows significantly over time, and as developed countries continue to see an increase in lifespan, the cost of cardiovascular healthcare for the elderly will undoubtedly rise. The molecular basis for cardiac function deterioration with age is multifaceted and not entirely clear, and there is a limit to what investigations can be performed on human subjects or mammalian models. Drosophila melanogaster has emerged as a useful model organism for studying aging in a short timeframe, benefitting from a suite of molecular and genetic tools and displaying highly conserved traits of cardiac senescence. Here, we discuss recent advances in our understanding of cardiac aging and how the fruit fly has aided in these developments.     

Metamorphosis and adult development of the mushroom bodies of the red flour beetle, Tribolium castaneum

The insect mushroom bodies play important roles in a number of higher processing functions such as sensory integration, higher level olfactory processing, and spatial and associative learning and memory. These functions have been established through studies in a handful of tractable model systems, of which only the fruit fly Drosophila melanogaster has been readily amenable to genetic manipulations. The red flour beetle Tribolium castaneum has a sequenced genome and has been subject to the development of molecular tools for the ready manipulation of gene expression; however, little is known about the development and organization of the mushroom bodies of this insect. The present account bridges this gap by demonstrating that the organization of the Tribolium mushroom bodies is strikingly like that of the fruit fly, with the significant exception that the timeline of neurogenesis is shifted so that the last population of Kenyon cells is born entirely after adult eclosion. Tribolium Kenyon cells are generated by two large neuroblasts per hemisphere and segregate into an early-born delta lobe subpopulation followed by clear homologs of the Drosophila gamma, alpha'/beta' and alpha/beta lobe subpopulations, with the larval-born cohorts undergoing dendritic reorganization during metamorphosis. BrdU labeling and immunohistochemical staining also reveal that a proportion of individual Tribolium have variable numbers of mushroom body neuroblasts. If heritable, this variation represents a unique opportunity for further studies of the genetic control of brain region size through the control of neuroblast number and cell cycle dynamics.