The “Organ-Disease”.
Abstract
The fruit fly, Drosophila melanogaster (Meigen, 1830) has been established as a key model organism thanks in part to their considerable biological similarity to mammals and an abundance of available genetic tools. Drosophila have been used to model many human disease states and have been critical in elucidating the genetic mechanisms contributing to them. Part I of this chapter covered basic Drosophila biology and relevant genetic tools available to Drosophila researchers. Here in part II, we review the use of Drosophila as a model organism to study neurodegenerative disorders, cardiovascular diseases, kidney diseases, cancer, metabolic disorders, and immune disorders, as well as key findings made in those fields thanks to Drosophila research.
Keywords
- animal model
- cancer
- diseases
- Drosophila
- genetic techniques
- heart
- immunology
- kidney
- metabolic disorders
- neurodegeneration
1. Introduction
Please refer to the Introduction of Part I, The fruit fly,
In this two-part chapter, some of the many aspects that make
Part I covered the basic fly biology and key genetic tools.
Here, Part II provides an overview of important disease states that
2. Drosophila melanogaster as model to study human diseases
Organ system | Diseases |
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The Drosophila brain is two-lobed and contains approximately 100,000 neurons. It is organized into several main structures including: supraesophageal ganglion (optic lobes and cerebrum) and a subesophageal ganglion. Flies also have a segmented nerve cord similar to a mammalian spinal cord (FLYBRAIN neuron Database) |
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Circulating immune cells called hemocytes (consisting of plasmatocytes, lamellocytes, and crystal cells) fight pathogens by encapsulating them, generating ROS, and/or producing antimicrobial peptides (AMPs). Many tissues are also capable of generating AMPs including the gut and fat body [72] |
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Consists of mouth parts for chewing, salivary glands to produce saliva, a crop (similar to a stomach), the proventriculus for grinding food, and a gut (midgut and hindgut) for digestion and nutrient and water absorption |
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Structures called Malpighian tubules and nephrocytes function similar to kidneys and filter nitrogenous waste from hemolymph. The tubules connect to the hindgut and excretory waste is eliminated along with digestive waste in the form of uric acid |
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Flies store glycogen and triglycerides in a specialized structure called the fat body. The fat body has functions similar to the mammalian liver and adipose tissue and is heavily involved in regulating growth, metabolism, and the immune system [16, 73, 74, 75]. |
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Flies have ovaries for egg production in females, and testes for sperm production in males. These structures develop from imaginal discs in the larva. A fertile female fly can lay hundreds of eggs |
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Flies have an exoskeleton composed mostly of a chitinous cuticle and an outer waxy coating. The cuticle is produced by epithelial cells and can be hard like bone or softer (as in the case of larvae). Muscles attach to points inside the exoskeleton and allow the fly to move |
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2.1. Neurodegenerative disorders
The
In order to characterize neuronal dysfunction in
Tauopathies, including Alzheimer’s, Parkinson’s, and others, refer to disorders caused by aberrant accumulation of the microtubule-associated protein tau [30].
2.2. Cardiovascular diseases
Even if most studies are based on the embryonic development of the fly heart, nowadays the focus is shifting to the function and structure of the
Several assay systems are helpful in characterizing
2.3. Kidney diseases
Despite millions of people suffering from kidney disorders, there is a disconcerting lack of therapies available to patients because the primary causes of kidney disorders are not completely characterized.
The insect Malpighian tubules and the nephrocytes are functionally analogous to the vertebrate kidney; in fact, these two organs in
Nephrotic syndrome refers to ultrafiltration dysfunction leading mostly to extra protein in the urine and deficiency of protein in blood [73]. Given the evolutionary conservation of the diaphragms and their regulative mechanisms,
The similarities among the species definitely allow the use of the
2.4. Cancer and growth
The fly is a simple model to improve the understanding of tumor biology and progression [79, 80, 81, 82, 83] as the available genetic tools support the analysis of the mechanisms underlying growth regulation in an intact epithelium rather than in cell cultures. The advantage is remarkable since cell-cell and cell-environment interactions contribute to tissue size regulation. The
A great conservation across species is detected in regards to the signaling pathways affecting growth. Initial studies using activated proto-oncogenes such as the receptor tyrosine kinase (
New studies defined how the loss of cell polarity could be considered a hallmark of malignancy [96]. Members of discs large (dlg) and lethal giant larvae (lgl) were identified as tumor suppressors in the fly by promoting cell invasion if mutated, with a similar role also seen in human neoplasm [97]. The role of proteins involved in cellular adhesion, such as Rho1 and E-cadherin, was also shown to be conserved and relevant for migration and invasion helping the study of the metastatic process [98, 99]. Other well-studied oncogenes in
As anticipated, the communication between neighboring cells must be taken into consideration when analyzing a tumor tissue. Competitive interactions occur among cells with different growth rates in a process known as cell competition, which was first described in
More studies are arising on the connection between the insurgence of tumors and diet or obesity. Recent studies linked the growth of prostate tumors and the status of obesity [113]. Caloric restriction reduces the growth of tumor cells in rodent models through reduced systemic insulin and IGF-1 signaling [114], while the activation of PI3K induces tumors to be resistant to diet restriction [115] suggesting an important relationship between PI3K signaling in tumors and the nutrients in the tumor environment. The exact link between obesity and cancer has not yet been established and the fly may facilitate this research thanks to the ability to combine obesity and tumor models in
2.5. Metabolic disorders
Hepatic diseases affect a large proportion of the population worldwide making it crucial to investigate the underlying pathogenic mechanisms that still remain unclear. Identification of the molecular defects underlying liver disease requires studies in model organisms, and recently
The use of the fruit fly in the study of hepatic disorders is partially restricted due to the absence of a homologous organ for the liver. The fat body in
It is necessary to improve assays examining the function of the fat body and oenocytes to solidify
Several proteins that contribute to lipid metabolism in
2.6. Immunological diseases
The mechanism of the innate immune system is fairly conserved across species, and
Some fly macrophages originate via self-renewing and others from progenitor cells that are located in the lymph gland, a specialized hematopoietic organ. The great importance of the lymph gland in controlling the blood cell homeostasis makes this
The great availability of genetic tools in the fly contributed to defining the innate immune system and to establishing that it is a specific mechanism. In fact,
In order to examine immunity in the fly, an efficient and simple procedure has been developed to elucidate the physiological effect after infection and to quantify the pathogen load. It consists in scoring bacterial load, fly mortality, and also evaluating the effect on immune transcription factors after the direct introduction of bacteria in the fly body cavity, eluding the epithelial barrier [164].
The innate immunity contributes to
3. Conclusions
As illustrated throughout these two chapters,
Acknowledgments
We thanks the Confocal facility at IFOM-Milan, Matteo Cascinelli, Matteo Frattaroli, Valeria Lupi, and John Benedict Pollard from Liceo Scientifico “A. Einstein Milano” and Zhasmine Mirzoyan University of Milan for helping with the images. Funding from Cariplo Foundation and EHDN to PB and from CiBio to MTC.
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