Drosophila Melanogaster: a Fly Through Its History and Current Use

Drosophila melanogaster: a fly through its history and current use

1R Stephenson, 2NH Metcalfe 1Fifth year medical student at Hull York Medical School; 2General Practioner, York and Lead of History of Modern Medicine SSC, Hull York Medical School, University of York, UK

ABSTRACT Drosophila melanogaster, the common fruit fly, has been used as a model Correspondence to R Stephenson, organism in both medical and scientific research for over a century. Work by 43 Breamish Drive, Thomas Hunt Morgan (1866–1945) and his students at Columbia University at the Rickleton, Washington, Tyne and Wear NE38 9HS, UK beginning of the twentieth century led to great discoveries such as sex-linked inheritance and that ionising radiation causes mutations in genes. However, the use tel. +44 (0)789 172 3688 of Drosophila was not limited to genetic research. Experimentation with this model e-mail [email protected] organism has also led to discoveries in neuroscience and neurodevelopment, including the basis of circadian rhythms. Its complex nervous system, conserved neurological function, and human disease-related loci allow Drosophila to be an ideal model organism for the study of neurodegenerative disease, for which it is used today, aiding research into diseases such as Alzheimer’s and Parkinson’s, which are becoming more prevalent in today’s ageing population.

Keywords Drosophila melanogaster, Thomas Hunt Morgan, Alfred Henry Sturtevant, Hermann Joseph Muller, Notch pathway, neurodegenerative disease

Declarations of Interests No conflicts of interest declared.

The use of Drosophila melanogaster in system that allows it to elicit complex neuronal tasks, medical and scientific research such as learning and memory, similar to that in humans.3 This nervous system consists of around 100,000 From their ancestral home in equatorial Africa1 to neurones and, despite the brain of a fly having a different laboratory benches throughout the world, Drosophila anatomical structure to that of a human, many key melanogaster (Figure 1) are one of the most valuable features of the development and function of this system model organisms in the world of neuroscience; but what remain the same.4 This includes conservation of is it that makes them an ideal model organism for fundamental cell biology such as membrane trafficking, research? Since being employed as a transgenic model regulation of gene expression and cell death, which are for spinocerebellar ataxia 3 (SCA3) in 1998, Drosophila present in all vertebrate systems.5 In fact, 75% of human have been used in the study of a wide range of human disease-related loci have a Drosophila orthologue.6 neurodegenerative diseases including Huntington’s, Another key feature making Drosophila an attractive Alzheimer’s and Parkinson’s disease (PD).2 This is model is the range of genetic tools (including the GAL4 possible because the fly possesses a complex nervous [a transcriptional activator in yeast]/UAS [upstream activating system], mosaic analysis with a repressible cell marker [MARCM] system and ribonucleic acid interface [RNAi]) available to manipulate them and the ease of introducing human genes into the fly. Its other benefits include being much less costly and time consuming to use than a mouse model for example,3 due to their rapid reproduction time and short lifespan, giving a higher throughput in experiments. Being able to introduce human genes into Drosophila enables us to recapitulate the symptoms and progression of human disease in flies.

From a common pest to Thomas Hunt Morgan and his students history Following the discovery of the white gene by Thomas figure 1 A Drosophila melanogaster fly (image courtesy Hunt Morgan (Figure 2) over 100 years ago, fruit flies of Chris Elliot). have been making important contributions to many

70 history 71 for for

8 Drosophila at melanogaster Drosophila It seems likely however that Lutz however likely It seems with drawings of with drawings melanogaster Drosophila 9 9 his original research eventually resulted resulted eventually research original his 8 Thomas Hunt Morgan (1866–1945) working in (1866–1945) working Hunt Morgan Thomas

. Drosophila figure 2 figure these flies behind him. (Image courtesy of the Wellcome Wellcome courtesy (Image the of flies behind him. these London.) Library, his laboratory on Morgan began his work with work his began Morgan In what became known York. New Columbia University, room’, fly ‘the as NCE SEX-LINKED INHERITA red-eyed of culture a breeding After almost a year, Morgan found a male fly with white eyes. with white eyes. fly male a found Morgan year, a almost with one of its red- male fly this white-eyed He bred eyes in 1,237 flies with red sisters which resulted eyed It was furtherthat all white- noted with white. three and additional and this of result a As male. were flies eyed further of these first inbreeding experiments involving this that thought initially he offspring, generation be limited to the male sex only. characteristic must in the complete DNA sequencing of all euchromatic in the complete DNA sequencing of all euchromatic in 2000. chromosomes of Drosophila regions gain valid data or make valid conclusions and stopped and conclusions valid or make valid data gain using recommended their use to Morgan in 1906, whose work work whose in 1906, Morgan to their use recommended in advances great produced with this model organism genetic research.

, Drosophila melanogaster: a fly through its history its fly through a use current and melanogaster: Drosophila in into his In this In 9 Drosophila . He looked He looked . as melanogaster including gene including 7

Drosophila Drosophila in this melanogaster Drosophila in research to a network of to a network in research 2013; 43:70–5 2013; has considerably improved improved considerably has melanogaster 2 Collectively, this work has formed a good basis good a formed has this work Collectively, 7 Drosophila J R Coll Physicians Edinb Coll Physicians J R © 2013 RCPE a model organism. During this time, there were also were there time, this During organism. model a neurodevelopment and neuroscience in discoveries the importanceNotch in embryonic of the including: the in 1915; DF Poulson identified by development, in to be involved found later genes detection of many Christiane Nüsslein- by conserved pathways signalling the basis of circadian and Wieschaus; and Eric Volhard late in the Benzer Seymour by described rhythms 1960s. work. He had already used wild crickets as model as crickets wild used already had He work. in variation the studied which he through organisms this research but he set shortforms, long-winged and of Drosophila aside to study the development larval the egg, through the development at specifically whether it was aimed to establish and pupal stages and or traits inherited characteristics, individual of result a due to the great Unfortunately, factors. environmental to he struggled rates at all stages, variation in growth work he anticipated a negative result and therefore saw saw and therefore result he anticipated a negative work breeding slower which were point in using mammals no chose he therefore expensive; more and which were fast breeding and cheaper. In 1903, Castle’s Castle’s In 1903, cheaper. and breeding fast which were a (1871–1947), William J Moenkhaus influenced work who School, Medical University at Indiana professor following into his laboratory, the fruit fly introduced including organisms in higher model experimental failures the entomologist Later, beetles. mice and willow fish, Experimental Evolution at the Station for Frank E Lutz, at the Carnegie Institution (Cold Spring Harbour) took incorporated and advice Moenkhaus’ to introduce was a movement 1900s there In the early into laboratories. organisms model experimental new to use Drosophila The first person for further neuroscientific research and Drosophila research furtherfor neuroscientific is still valuable model one of the most melanogaster research day Present 3). (Figure today used organisms using concepts underlying of the molecular our understanding polyglutamine including diseases neurodegenerative becoming which are PD, and disease Alzheimer’s diseases, of the populations the ageing concern to of increasing world. Western professor a (1867–1962), WilliamCastle Ernest was way the disseminate to on went he Harvardat University; idea of using Drosophila first used Drosophila Castle experimental zoologists. on the genetics into his work them incorporating 1901, pigs. guinea and mice both in coat-colour of biology, cell biology, developmental biology and developmental cell biology, biology, Morgan’s work, his by Influenced genetics. population Henry Alfred Sturtevant (1891–1970), students, three Muller Joseph Hermann (1889–1938) and Calvin Bridges in genetics. advances make to on went (1890–1967), appreciate to scientists the only not were these However, using of the potential benefits fields of medical and scientific and scientific fields of medical research, R Stephenson, NH Metcalfe

Thomas H Morgan The ‘fly room’ Hermann J Muller Nusslein-Volhard and Nobel prize: ionising Wieschaus: Embryonic William E Castle radiation-inducing development of nervous Alzheimer’s disease Genetics of coat-colour mutations system Parkinson’s disease

1901 1903 1906 1915 1946 1960s–70s mid 1970s 1998 Today

William J Moenkhaus Notch pathway Benzer Model of SCA3 Circadian rhythms

figure 3 Timeline of the use of Drosophila melanogaster in the history of medical and scientific research

However, further inbreeding of a white-eyed male fly Important discoveries in neuroscience with some of its daughter flies resulted in white-eyed using Drosophila female offspring. This suggested that this trait was not limited to the male sex.10 His research led him to Notch conclude that the white-eye characteristic, which he named the white gene, must be carried on the X Research using Drosophila melanogaster uncovered some chromosome11 which, in turn, led to the discovery of key aspects of neurodevelopment, including the discovery sex-linked inheritance.12 of Notch and its mutations. In higher vertebrates, it is now known that the Notch signalling pathway determines Following the work by Morgan, one of his students, cell fate during development. It is involved in cell identity, Alfred Henry Sturtevant, recognised that the sex-linked as well as differentiation, proliferation and eventual factors Morgan described might be arranged linearly.12 apoptosis of cells, also creating a boundary between cell By breeding groups of Drosophila with dissimilar populations allowing development.17 phenotypes resulting from different mutations, Sturtevant found that sections of homologous chromosomes could Mutations in Notch were first identified in 1915 and the interchange, or as he termed it, ‘cross-over’. He assumed following year it was first reported that these mutations that the proportion of ‘cross-overs’ indicated the caused malformations of Drosophila wings.7 DF Poulson, distance between them13 and consequently, from the five a professor at Yale University, was the first to identify sex-linked mutations described by Morgan, he assembled links between Notch and neurogenic development. a genetic map.12 Poulson found that deletion of the Notch gene resulted in a hypertrophied central nervous system as a IONISING RADIATION AND MUTATIONS consequence of embryonic hypoderm differentiating into neuroblasts. Later the human NOTCH gene was Hermann Joseph Muller was another of Morgan’s cloned as part of research into human leukaemia and students at Columbia University. It was later in his mutations in Notch were thought to be a causative career, while working at the University of Texas, that he factor. The cloning of this gene demonstrated how the discovered that radiation could produce genetic Notch gene and all components of the Notch pathway mutations.14 He won the Nobel Prize in 1946 in in Drosophila are conserved to higher vertebrates. The Physiology or Medicine for the conclusion that ionising discovery of Notch in Drosophila and consequent radiation causes mutations such as chromosomal further research into the Notch pathway has highlighted rearrangements.15 Muller reported in his article entitled its involvement in neurogenesis and neurone Artificial Transmutation of the Gene published in 1927, differentiation and, consequently, its overall importance that treating the sperm of Drosophila with X-rays in developmental neurobiology. In addition, it has been produced mutations in genes that were stably inherited implicated in learning and memory, which can also be and could be followed through three or four further demonstrated in adult flies. After further research, it is generations. Additionally, he found that there was a now known that Notch plays a significant role in dose-response relationship between the dose of X-rays neuronal development and is also a major part of and number of mutations. Treated flies had a mutation development of the heart, blood cells, skin and bone.7 rate of up to 150-fold greater than control flies bred in the same conditions. He also reported changes in the CIRCADIAN RHYTHMS linear arrangements of genes as a result of X-ray history treatment, including inversions, translocations and Work by Seymour Benzer (1921–2007) in the 1960– fragmentations.16 70s first formed the basis of our understanding of circadian rhythms. He designed the light countercurrent

24 73 has allowed has allowed has led to has provide provide melanogaster . It is a a is It . melanogaster 24 Agrawal et al. introduced introduced al. et Agrawal

understood to be caused by to be caused by understood Drosophila 23

20 Homologues of the huntingtin of Homologues 21 , they identified two combination two identified they , Drosophila Further work using Drosophila Further work 22 and into Drosophila human huntingtin protein mutant survival through neurodegeneration widespread analysed used They and climbing assays. pseudopupil assays assays, of effects the assess to experiments drug-feeding and on disease progression combination drug regimens red, tested (Congo regimens concluded that the two cystamine and SAHA or SAHA combined with neurodegeneration suppressed Y-27632) or geldanamycin in symptoms in reducing be effective may and therefore disease. people with Huntington’s conclusions that while the huntingtin protein is normally is normally huntingtin protein that while the conclusions localised are forms mutated localised to the cytoplasm, large which are inclusions, addition, In nucleus. the to transcriptional and protein of the mutated aggregates to the contributing in neurones found are co-activators, pathologydisease.this of proposed the effectiveness of combination drug regimens of combination drug regimens the effectiveness proposed their through disease; in the management of Huntington’s with work as potential candidates. regimens Alzheimer’s disease Alzheimer’s disease is becoming an ever-increasing Alzheimer’s particularlypopulation of the with the ageing problem, to needed therefore is Further research world. Western develop to and the disease us in understanding aid Not only does the use of use the does only Not Features of SCA3 were reflected in these diseased flies, flies, in these diseased reflected of SCA3 were Features used in further to be model organism this for allowing and of degeneration the mechanisms into research in SCA3.loss neuronal protein have been found in other vertebrates including in other vertebrates been found have protein but because of the and zebrafish, pufferfish mice, of functional domains similarity in amino acid sequence, Studies distinguished. be easily not could the protein Drosophila related distantly using the more are that domains conservedidentification of protein for huntingtin the of function in the significant be to likely protein. Huntington’s disease Huntington’s has that disease polyglutamine another is Huntington’s Drosophila using studied been neurodegenerative disorder that has autosomal autosomal has that disorder neurodegenerative by characterised and is clinically dominant inheritance time, that deteriorate over movements choreic psychiatric and decline cognitive by accompanied It is currently disturbances. of expansion at the N-terminus abnormal polyglutamine 36 repeats Expansion beyond the huntingtin protein. in found huntingtin protein in the neurotoxic results disease. Huntington’s insight into the aetiology and pathogenesis of Huntington’s insight into the aetiology and pathogenesis of Huntington’s into opportunities research for provides also it disease, et al. Agrawal A study by intervention. therapeutic Drosophila melanogaster: a fly through its history its fly through a use current and melanogaster: Drosophila typically typically STEM 7 have have melanogaster

Y S S VOU C YONI tential uses for Drosophila

EMBR 18 All these diseases are progressive progressive are diseases All these 19 model of SCA3model in created was 2013; 43:70–5 2013; . In this assay he quantitatively he quantitatively In this assay . and po

7 Spinocerebellar ataxia type 3 type ataxia Spinocerebellar 20 Drosophila This aetiological process is common to all the is common This aetiological process 18 OGENESIS AND Elongated polyglutamine proteins (disease (disease proteins polyglutamine Elongated 2 osophila J R Coll Physicians Edinb Coll Physicians J R © 2013 RCPE TR HE NE OF DEVELOPMENT presents with dysarthria and both limb and gait ataxia, with dysarthria ataxia, gait both limb and and presents time. over deteriorating been used to demonstrate these diseases; the first the diseases; these demonstrate to used been transgenic 1998. proteins similar to that in human disease) 78 residues 78 residues disease) in human that similar to proteins the SCA3into the flies using gene introduced were long expressing with controls compared these flies were and 27 residues. only of runs with polyglutamine proteins polyglutamine diseases, which also include Huntington’s which also include Huntington’s diseases, polyglutamine (SBMA), atrophy spinal and bulbar muscular disease, of types many (DRPLA) and dentatorubral-pallidoluysian ataxia. spinocerebellar and neurodegenerative. However the pattern of of pattern the However neurodegenerative. and differs the clinical features and therefore degeneration them. between Spinocerebellar ataxia 3 ataxia Spinocerebellar (SCA33 type ataxia Machado-Joseph Spinocerebellar or dominant inherited disease disease) is an autosomal, specific at trinucleotide CAG the of repeats by caused the in result that 14, chromosome on loci gene portionelongation of the polyglutamine ataxin-3 of the protein. The current In the mid-1970s, further research into neurogenesis neurogenesis into further research mid-1970s, the In nervous of the system and embryonic development as the main again using Drosophila out, was carried mutagenesis chemical Systematic organism. model flies, of chromosomes the on out carried were screens neurogenesis in involved genes identifying of aim the with (a Nüsslein-Volhard and embryonic development. American (an Wieschaus and biologist) German identified 139 genes involved biologist), developmental larval that control development. in signalling pathways Hedgehog Wingless, included These signalling pathways be to found were factor and growth Tumour and partas of conservedvertebrates, higher to and neurogenesis stem cells, of neuronal differentiation of the in the development migration of neurones nervous system. Dr NEUR assay, still used in research today, as a simple behavioural behavioural simple a as today, research in used still assay, test in Drosophila light a to flies of responses behavioural the measured with responses these then compared He stimulus. with faulty those including flies, mutant of those and those with X-chromosome phototaxis mechanisms on identified and then published a paper He mutations. rhythms. to circadian the key the period (per) gene: homologous that later years many was it However mice and humans. in found genes were R Stephenson, NH Metcalfe

interventions in the future. Drosophila melanogaster is an active metabolite of MPTP, which can cause mitochondrial ideal model organism to demonstrate Alzheimer’s defects.28 However 5–10% of PD cases appear to have disease as it can be crafted to show the signs of the familial aetiology linked to the following genes: progressive neuronal degeneration seen in this disease. α-synuclein, DJ-1, Parkin, PINK1 and LRRK2. These have The pathology involves formation of β-amyloid plaques both recessive and dominant inheritance. Understanding composed of amyloid β1-42 and neurofibrillary tangles of these genetic components has led to further formed from hyperphosphorylated tau protein. Using awareness of the molecular pathogenesis of this disease.26 genetic modification methods, such as the Gal4/UAS Drosophila melanogaster are being used today in the study system, we can engineer Drosophila to manufacture of these familial causes of PD.

amyloid β1–42 and therefore amyloid plaques, giving a fly the equivalent of Alzheimer’s disease in humans. The One of the genes linked to familial PD, α-synuclein, is not Gal4/UAS system can also be used to introduce R406W, found in Drosophila. This gene encodes a protein which is the tauopathy-associated mutant of human tau, into a component of Lewy bodies that are implicated in the Drosophila to replicate neurofibrillary tangles in a similar pathology of PD.30 Feany and Bender31 introduced human way. Assessment of these transgenic flies through α-synuclein into Drosophila using the GAL4/UAS system longevity assays, locomotor and climbing assays and to demonstrate neuronal degeneration, formation of olfactory learning assays allows for further assessment inclusions and resultant defects in locomotion caused by of how Alzheimer’s disease affects humans. Progressive α-synuclein toxicity. They used tyrosine hydroxylase locomotor decline can be observed in transgenic staining to analyse the dopaminergic neurones in sections Drosophila through climbing assays. In addition, the of the fly brain, looking directly for neurodegeneration crawling velocity of larvae can be measured to assess and used climbing assays to analyse the correlating the effects of tau phosphorylation on motor neurones. locomotor response.31 Climbing assays were also used by Pavlovian olfactory learning assays, in which the Greene et al.31 in their study of parkin, mutations in Drosophila associated a certain odour with an electric which were already known to cause a form of early onset shock and therefore learn to move towards the control PD called autosomal recessive juvenile parkinsonism. odour in a T-maze, have shown impaired learning in flies They studied the longevity, flight and climbing abilities of

containing Aβ1–42. Histological assays demonstrate the Drosophila containing mutant parkin. Results demonstrated changes that occur at the neuronal level at different reduced longevity and defects in flight and climbing, as stages of the disease progression. The use of Drosophila well as male sterility. As changes in the structure of melanogaster in Alzheimer’s disease research allows mitochondria are a common feature of both muscle and further understanding and potential discovery of new germline pathology, they concluded that mitochondrial pathological processes and identification of new dysfunction must be significant in the mechanism of molecular targets for therapeutic development.25 dopaminergic neuronal loss in PD.32

Parkinson’s disease Conclusion

Another progressive neurodegenerative disease for Drosophila melanogaster, or the common fruit fly, has which Drosophila melanogaster have been key in research been important in the study of genetics for over 100 and pathological development is PD. It is a chronic, years and neuroscience for less than that.7 Work by progressive neurodegenerative disorder with worldwide Thomas Hunt Morgan and his students led to great distribution and increasing incidence with age.26 James advances in genetics including the construction of a Parkinson (1755–1844), an English apothecary and genetic map and the recognition that ionising radiation surgeon, first described this disease in his 1817 monograph is a causative factor in genetic mutations.15 Further Essay of the Shaking Palsy,27 in which he outlined the core insight into neurodevelopment and therefore functioning clinical manifestations28 of this physically and socially of the nervous system has been influenced significantly debilitating disease.26 These include resting tremor, by work done in Drosophila melanogaster,7 leading to the postural instability, muscular rigidity, bradykinesia and gait research carried out today into neurodegenerative difficulties. The pathology of PD arises from progressive diseases such as Alzheimer’s disease and PD. With the loss of dopaminergic neurones in the substantia nigra ageing population of the Western World, further research pars compacta (SNc).29 into these diseases will be greatly influential and aided much by Drosophila melanogaster. The majority of cases of PD are sporadic, with unknown Acknowledgement aetiology. The environmental hypothesis suggests that these cases result from exposure to dopaminergic We are grateful for permission from Chris Elliot, neurotoxins in the environment such as paraquat and University of York for use of Figure 1 and the Wellcome history rotenone, used as an herbicide and an insecticide Library, London for use of Figure 2. respectively. Both are structurally similar to MPP+, the

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