DROSOPHILA MELANOGASTER MODEL IN STUDY HUMAN DISEASES

Tap chi Cong nghe Sinh hgc 10(4): 601-608. 2012

DROSOPHILA MELANOGASTER MODEL IN STUDY HUMAN DISEASES

Dang Thi Phuong Thao, Tran Linh Thuoc

University of Science. Viemam National University in Ho Chi Minh City

SUMMARY

Charles Darwin with the Origin of Species in middle 19lh century and Gregor Mendel with expenments in pea plants had succesfiilly created a base for using organism model m study on biological processing and regulation. From 20th century, animal models has been gotten more important for research on human biology.

Among of the animal models, mouse model is most widely used in study on human genetics and diseases.

However, we have lo spend quite a lost of money and time when using mouse model. In 1900s, Thomas Hunt Morgan had used Drosopliila melanogasier as model in his expenments The Drosophila model showing many good points for screening disease- related genes with low cost and Ume comsummg, provides us a good tool to modeling human disease related gene network Thus, it is useful model organisms for understanding many molecular and cellular mechanisms of human disease. Many aspects of human disease, and of defences againsl disease, are also found in flies. These include cancer, ageing, n euro degeneration, infectious disease, innate immunity, cardiovascular disease, metabolism disease, diabete etc. Although Drosophila model has been widely used in the world, it's quite new in Vietnam so far. From 2008, our department has introduced a new branch of research and gotten several good results in research with the DrosophiUi model. Based on it, here we review either on pnnciple of establishing transgenic flies or use of fly model in sludy human diseases This review aims to bnng such a usefitl research model more close to Vietnamese scientists and introduces basically techniques for setting up research on the benefit model in Vietnam

Keywords: Drosophila model, transgenic fi\, human di \ease model, Gal4- UAS .s_ I. P-elemenI Iransgene BENEFITS OF DROSOPHILA AS MODEL IN

RESEARCH

The genetically modified mouse model has been widely used lo study human diseases. However, this model has high cost and time consuming. One of the biological models can be used, as a model for human diseases is the genetically modified fruit fly, Drosophila. This is an effective model for wide screening disease genes with low cost and time saving. In this model, scientists can study and mimic clearly the related genes, and modulate the disease gene. The genetically modified fruit fly model has been used widely in human disease researches such as neurodegenerative diseases (Auluck et a l , 2002, Auluck, Bonini, 2002; Bilen. Bonini, 2005; Feany, Bender, 2000; Finelli el al., 2004). metabolism diseases (Baker. Thummel, 2007; Haselton et al, 2010), aging and cardiovascular diseases (Ocorr et al.. 2007. Reim, Frasch, 2010), cancer (Pagliarini.

Xu, 2003), diabetes (DiAngelo, Bimbaum. 2009).

The reasons wh\ many researchers choose Drosophila as model in their experiments are following'

Short life cycle and easy maintenance Drosophila life cycle is short The fly is getting mature 2 weeks after hatching Female flies sexually mature 12 hours after hatching and lay eggs al 2 days age with high reproduction ability. One female fly can lay 100 eggs/day and 2000 eggs in whole life span (Rubin, Lewis. 2000). It is easy to distinguish male and female at young stage, consequently it enables an open door for carrying out crossing experiments to get progenies (Dahmann, 2008) Finally, there is no ethical restriction in making experiments using insects and a low cost of Drosophila maintenance allow us to set a thousand of individual experiments at the same time Together, those above advantages give a high possibility to do large-scale genetic and physical screening in Drosophila model (Rubm, Lewis, 2000).

Genetically advantages

Drosophila has 4 chromosome sets. 1 of ihem is sex chromosome. Whole Drosophila genome was completely sequenced in 2000 showing an existence

601

Dang Thi Phuong Thao & Tran Linh Thuoc of more than 75% orthologues of human disease

related genes in Drosophila (Adam et al., 2000). It created the most important reason made Drosophila as good model in studying human diseases.

Furthermore, the conscr\'ation of Drosophila amino acid sequences is much higher than those of other organism models such as nematode and yeast More than 50% protein in Drosophila has high identity to protein in mammalian. Besides, Drosophila has many mutant phenotypes, which usefijl for screening and analyzing on transgenic flies (Dahmann, 2008), Drosophila salivary gland has giant chrosome which provides a good tool for research on molecular genetic, gene function and mapping (Rubin, Lewis, 2000; Dahmann, 2008). Finally, mammalian genes usually form families, but Drosophila genes usually do not. The single form of genes in Drosophila enables a high possibility in study gene function without disturbance signal, which may come from other family genes (Rubin, Lewis, 2000)

Although Drosophila model shows many benefits in using as human disease model, it still has some weak points in comparison to other mammalian model, specially for the similarity of genes and some biopathways. That is why Dro.wphila is good in using as fundametal screening

in large-scale before using of other mammalian models.

UAS-GAL4, A TOOL FOR TISSUE SPECIFIC GENE EXPRESSION IN TRANSGENIC DROSOPHILA

Gal4 IS a protein with 881 amino acids, originally found in Saccharomyces cerevisiae It binds to the Upstream Activating Sequences (UAS) and act as an enhancer to activate transcription of the down stream gene. In 1988 Fischer showed that Gal4 play the same way with UAS in Drosophila and has no bad effects in the organism (Phelps. Brand, 1998).

The basic principle of UAS-Gal4 system in transgenic flies is figured as following: Normally, Gal4 follows tissue specific promoter and stays independently to UAS sequence in transgenic fly.

Target gene is flised down stream of UAS sequence and located in different transgenic fly lines. To activate Gal4-UAS system, progeny from the two transgenic flies IS used. Whenever Gal4 is expressed in tissue under nssue specific driver, the Gal4 binds to UAS sequence and activates target gene transcription (Fig.

I). There are various Gal4 tissue specific dnvers available in Drosophila stock center (Table 1)

Figure L UAS-GAL4 system in Drosophila 602

Tgp chi Cong ngh4 Sinh hgc 10(4): 601-608, 2012

Table 1. Some common use Gal4 tissue specific dnvers Target tissue/cell Act5c-GAL4

GMR-GAL4 Ddc-GAL4 Mef-GAL4 Ap-GAL4 N0S-GAL4 TH-GAL4 Cha-GAL4 Elav-GAL4

Whole body Eye imaginal discs

Dopaminenc neuron cells and Serotonic neuron cells Muscle tissues

Wing imaginal discs Ovary

Tyrosine hydroxylase production neuron cells Choline production neuron cells Neuron cells

Not only useful in tissue specific gene expression for gain function studies. Gal4-UAS system is also helpful for lost function study via expression of dsRNA (double strands RNA) in specific tissues (Manfredsson et al., 2006).

GENE TRANSFER IN DROSOPHILA Nowadays, most of transgenic fly establishment were carried out based on P element vector, which contains modified transposon P cassette gene. The modified P element was cut down transposase gene for a stably of transgene in fly chromosome, Transposase enzyme is transiently transformed into fertilized fly eggs when we microinject P element vector to the fly eggs (Dahmann, 2008), However, it was either difficult lo control transposase amount or keep it stable in the micromjected eggs until gene transposition occurs. To solve the problem, scientists supported transposase via expression vector, which carries transposase gene and stays transiently in micromjected eggs as non-integrated plasmid (Dahmann, 2008).

The second important element for gene transferring in Drosophila is marker gene that allows us to screen transgenic files after microinjection. Normally, people uses ir* gene, giving red eye, as marker gene

To transfer target gene into Drosophila embryos, researchers microinject paralelly helper P-element vector, which carries transsposase gene, and donor vector thai contains target gene, w marker gene, 3 ' and 5' P element regions into fly germ cells. In the cells, transposase gene in the helper vector expresses. The expressed transposase recognizes the 3 ' 5 ' P element regions and activate gene-

transferring process to integrate target cassette gene into fly chromosome

DROSOPHILA MELANOGASTER IN STUDY HUMAN DISEASES

Drosophila in study neurodegenerative diseases Neurodegeneration diseases are age related diseases and caused by losing neural cells Some of neurodegeneration diseases such as Parkinson, Huntington are involved in accumulation of toxic protein in neural cells (Sang, Jackson. 2005, Nichols, 2006). Genetic analysis of identification and screening mutations that relate to the diseases is important to investigate molecular mechanisms and establish in vivo models lo study on the diseases Different to other animal models, D melanogasier serves a good model to do research on neurodegeneration diseases because of it short life span and similarity in neural system development.

Scientist can monitor their experiments irom early to late stage of the disease on Drosophila model (Bilen, Bonini, 2005)

Alzheimer (AD)

Most of AD genes have homologue in Drosophila, ex: APP gene in human has high similarity to Drosophila APP- like (APPL) Lack of APPL, Drosophila has abnormal phenotype with similar mechanism to AD patients y-secretase m D melanogasier is high conserved and involved in Notch signal transduction (Crowther et al, 2005) Parkinson

Parkinson Disease (PD) is a nervous degeneration disease, caused by the insufflcioni o f

Dang Thi Phuong Thao & Tran Linh Thuoc dopamine in the midbrain. Although this is a

common, wide spread and dangerous disease, studies on the disease's causes, preventions, mimicked research models, and treatments still have not yet given the expected resuhs- Many important questions about PD still do not have satisfied explanation.

Recent studies start to move to find single mutations related to the hereditary of several PD, help us to have clearer understanding on the molecular mechanism of PD through the establishment of research models using genetically modified animals carried PD phenotype (Auluck, Bonini, 2002;

Pendleton, 2002, Sherzer et al., 2003; Park et al., 2006; Sang et al., 2007). This method, not only can satisfy the requirements of biology molecular researches for the causing mechanism of the disease.

It can also help us to proceed to the screening for chemical substances which have curable activity (Auluck, Bonini, 2002; Nichols, 2006; Akasaka, Ocorr, 2009)

As mentioned above, nowadays, many researchers around the world have been using the fruit fly Drosophila as a model for studying and drug screenings based on mutations or modification genes like alpha-synuclein, parkin 1, Dj-1 and others (Akasaka, Ocorr, 2009), These researches, in some ways, clarified some phenomena related to Parkinson disease and introduced some chemical substances which have the potential in treatment the disease.

In our study, based on the fact that PD involved network have too many genes, proteins and the modulation mechanism, as well as the roles of genes and proteins are still not well understood. We have studied on role of U C H - L l . one of the proteins stated in the PD interesting groups need to be paid attention to, by using Drosophila. We so far have found that the dUCH, UCH-Ll homologue gene in Drosophila, plays very important function in cell differentiation, proliferation and apoptosis (Thao et al., 2012).

Triplet Repeat Expansion Diseases

Up to now. about 22 different neurological diseases are known as results of triplet repeated expansion in human genome. The clinical phenotypes of triplet repeat expansion diseases depend on the context of the protein where the repeat expansions occur (Higashiyama et al,, 2002; Jin et al.. 2007; Fujikake et a l , 2008). Polyglutamme diseases are caused by mutations that lead to hyperexpansions of unstable CAG repeats, which are

translated as glutamine in normal flinctioning proteins. Polyglutamine diseases are due to single- gene defects and were the fu-st neurodegenerative models successfiilly created in D. melanogasier.

There are several D. melanogasier models of tnplet repeat expansion diseases (Nagai et al., 2003;

Fujikake et al., 2008). All of these models demonstrated that increased poly-Gln expansion led to increased severity of degeneration, age-dependent degeneration, and repeat length-dependent protein aggregation. These models provided a platform to demonstrate that human disease genes can yield parallel neurodegenerative effects m D melanogasier

Seizure Disorders

D. melanogasier brain elicits seizure-like activity similar to all animals with complex nervous systems, including humans. Therefore, D.

melanogasier has been developed as a model to study seizure disorders. There is a collection of 11 seizure-sensitive D. melanogasier mutants (also know as BS, bang-sensitive, like mutants) that recapitulate key features of human seizures Although the BS mutant seizure physiology resembles that observed in mammals, the BS genes do not. however, correspond to known mammalian genes involved in seizure disorders. Nevertheless, there are significant similarities between human seizures and D. melanogasier seizure models, providing support for the utility of the D.

melanogasier model system for drug discovery. The importance of the D melanogasier seizure model has been further strengthened by the fact that seizure- like activity spreads through the fly CNS along particular pathways that are dependent on fiinctional synaptic connections and recent electrical activity, as do seizures in humans (Sang, Jackson, 2005; Furukubo, 2009; Cirelli, 2009).

Drosophila melanogasier in cancer research In the past, cancer research has been conducted almost exclusively in mammalian-based systems ranging from tissue culture to whole-animal studies.

Recently, however, the fly has been increasingly used as a model system. Perhaps one of the greatest contributions of the fly to the study of cancer biology was the elucidation of the Ras signal transduction cascade more than 20 years ago in the fly visual system (Reim, Frasch, 2010). The majority of cancers in humans are derived from epithelial cells (Aritakula, Ramasamy, 2008), making these types of

Tgp chi Cong nghe Sinh hoc 10(4): 601 -608, 2012 tumors significant targets for therapeutics.

Accordingly, there are a number of fly models being developed to study epithelial cell-derived cancers that could and are being translated to a discovery platform. These models include not only proliferative phenotypes but metastatic and invasive ones as well. Additional epithelial models using morphological changes in fly adult structural phenotypes have also been developed for discovery of molecules targeting the EOF receptor/ras pathway (Aritakula and Ramasamy, 2008), and E-cadherin (Pereira etal., 2006).

Nevertheless, there are limitations of the fly in cancer research. Whereas fundamental molecular mechanisms underlying tumor genesis and metastasis can probably be efficiently probed in D melanogasier, the fly is not able to mode! many types of tumors that are common in humans, such as those related to specific tissues (e.g., prostate, ovarian, or breast cancer).

Drosophila melanogaster in cardiovascular diseases research

Recent scientific reports have indicated thai the fly can be used successfully in the discovery process for cardiovascular diseases (CD), which are highly desirable area for development of new and more effective therapeutics. CD are multifactor disorders that involve heredity as well as environmental factors, and that whereas certain aspects of CD can be modeled in the fly to yield informative results, the inherently complex nature of the cardiovascular system in humans presents certain limitations in the fly for accurate modeling. Various forms of dysfunction that include structural defects, arrhythmias, and cardiomyopathies are known to occur in natural populations of flies (Ocorr et al., 2007). Many of these effects can be age-related, and even result in cardiac failure m the fly (Ocorr et al., 2007) Together, these aspects of the fly heart and its function indicate that the fly can be a valid model for the study of aspects of mammalian CD and an important tool in the process to discover new therapeutics (Sofola et a l , 2008)

Drosophila melanogaster in study infectious and inflammation diseases

D. melanogaster has a very sophisticated immune response thai current research demonstrates IS highly relevant to the understanding of human inflammatory conduions. Flies are constantly exposed lo pathogens within their environment.

largely in the form of bacteria, both as larvae and as adults. The Drosophila model, therefore, serves a good model for study the basic physiology of the inflammatory response and immune signaling (Botas, 2007; Ha et al., 2005). However, D.

melanogaster does not have an adaptive immune system. Therefore, there is significant limitation in using as appropriate model for the study of antibody and lymphocyte-dependent adaptive immune defenses.

The D. melanogaster model for asthma, which is the most common chronic inflammatory disease of the lung, is arguably the most advanced. There are many conserved genes and regulatory components between trachea development in the fly and lung development in mammals (Roeder et a l , 2009) Airway epithelial cells form the trachea, and they are the first line of defense against airborne pathogens. Un- like mammalian airways, the D, melanogaster trachea is much simpler and consists of only one type of epithelial cell (Roeder et al„ 2009).

Drosophila melanogaster in diabetes and metabolic diseases research

Recent advances in the understanding of metabolic processes, glucose homeostasis, and endocrinology in the fly have poised D.

melanogaster as a valid model relevant lo human metabolic disorders and diabetes thai can be used in the therapeutic discovery arena In the fly, there are neurosecretory cells (Lloyd, Taylor, 2010) in the brain that secrete insulin, as well as additional secretory cells that secrete a glucagon analog those together exhibit physiological and genetic parallels lo the vertebrate endocrine axis (DiAngelo, Bimbaum, 2009). Ablation of the adult insulin- secreting cells can lead to increased glucose levels in the hemolymph (the "blood" of the fly), increased circulating lipids, and resistance to starvation, among other phenotypes. Fat cells and the fat body m D.

melanogaster perform functions similar to those of the mammalian liver and are regulated by insulin through mechanisms conserved in mammalian systems in terras of metabolism and triglyceride and glycogen storage (DiAngelo and Bimbaum, 2009) Interestingly, flies deficient in insulin production demonstrate a delay in development as well as small body size, both as larvae and as adults (Haselton, Fridell, 2010). Therefore, flies may potentially be useful in the discovery, screening, and validation phases for diabetes and metabolic disorder therapeutics.

605

Dang Thi Phuong Thao & Tran Linh Thuoc CONCLUSIONS

Nowadays, many researchers around the world have been using the fi-uit fly Drosophila as a model for studying and drug screenings. These researches, in some ways, clarified that Drosophila is a good model for human disease researches.

Drosophila has been known and used by researchers all over the world as a hereditary research model, especially molecular hereditary diseases Many published papers based on Drosophila researches have been showed to have great contribution to human beings. However, the molecular hereditary models in Vietnam almost have not yet been well developed. We therefore, in this review, summarized research resuhs and advantages of the Dro.sophila mode! in order to take the essential research field, which had been established long time ago in many countries in the world, more close to Vietnam.

Acknowledgement: We are grateful to the Vietnam National University in Ho Chi Minh City, the Nalional Foundation for Science & Technology Development (Nafosted). Vietnam and the Kyoto Institute of Techonology for supporting our researclies on Drosophila model.

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Dang Thi Phuong Thao & Tran Linh Thuoc

M O HiNH DROSOPHILA MELANOGASTER TRONG NGHlfiN CtTU BENH TREN NGUOfI

Dang Thi Phirong Thao', Tr5n Linh Thu-ffc

Tnr&ng Dgi hgc Khoa hgc lir nhien, Dai hoc Quoc Gia Thdnh pho Ho Chi Minh

TOM T A T

GiiJa th^ ky 19, phat hien ciia Charles Darwin ve ngu6n goc cac Ioai va nhimg thi nghiem ciia Gregor Mendel tren dau Ha Lan da tao n^n tang cho viec sii dung cac smh vat phuc vu cho nghien cim cac quy luat cung nhu cac qua trinh sinh hgc. Ct thi ky 20, cac mo hinh dong vat dong vai tro ngay cang trd nen quan trgng trong nghien cim sinh hoc ngucn, trong do chugt chuyen gen da va dang dugc sir dung rgng rai de nghien ciiu cac benh tren nguoi Tuy nhien. mo hinh nay thuong chi phi cao cung nhu can mot khoang thai gian kha dai.

Dugc Thomas Hunt Morgan su dung tir nhimg nam 1900, ruoi giam Drosophila melanogaster la mo hinh dgng vat trong nghien ciiu voi nhieu uu diem, hihi ich cho viec sang Igc rgng rai cac gene gay benh vai chi phi thap va thoi gian ngin, mo phong hoa duoc mang luoi gen hen quan den benh tren nguoi. Chinh vi vay, mo hinh nay da va dang la mgt mo hinh hiru ich cho cac nghien ciiu cac co che benh tren nguoi o miic phan tit va te bao NhiSu trang thai benh tren nguoi cung nhu phirong thirc phong chong benh da dugc tim thay tren ruoi bao gflm. ung thu, lao hoa, thoai hoa thSn kinh, benh truyen nhilm, mien dich bam sinh, benh hm mach, benh li@n quan den r6i loan bi&n dirong, tieu dirong .. Mac dii mo hinh Drosophila da va dang duac sir dung rgng rai tren thi gioi, mo hinh nay con kha mai la tai Viet Nam. Tir nam 2008, bo mon chiing toi da bat dau nghien cihi va thu nhan duac mgt so ket qua kha quan tren mo hinh ruoi giam chuyen gen Tren ca so nay, chiing toi khai quat cac van de lien quan den ky thuat tao ruoi chuyen gen, cac thanh tuu sir dung ruoi chuyen gen nhir mo hinh nghien ciai benh tren nguoi. Bai tong quan nay khong chi mong muon dem mot mo hinh nghien ciiu huu ich nhu mo hinh ruoi giam chuyen gen den gan ban vai cong dong khoa hoc Viet Nam ma con gioi thieu cac nen tang ky thuat trong viec ihiet ke nghien ciiu tren mo hinh nay tai Viet Nam.

Tir khoa: Mo hinh Drosophila. nroi chuyen gen, mo hinh benh tren ngudi. Gal4-UAS system, P-element iransgene

' Author for correspondence: E-mail, lbaodiy@hcinus.edu v 608