Drosophila tools and assays for the study of human diseases

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ABSTRACT

Many of the internal organ systems of Drosophila melanogaster are functionally analogous to those in vertebrates, including humans. Although humans and flies differ greatly in terms of their gross morphological and cellular features, many of the molecular mechanisms that govern development and drive cellular and physiological processes are conserved between both organisms. The morphological differences are deceiving and have led researchers to undervalue the study of invertebrate organs in unraveling pathogenic mechanisms of diseases. In this review and accompanying poster, we highlight the physiological and molecular parallels between fly and human organs that validate the use of Drosophila to study the molecular pathogenesis underlying human diseases. We discuss assays that have been developed in flies to study the function of specific genes in the central nervous system, heart, liver and kidney, and provide examples of the use of these assays to address questions related to human diseases. These assays provide us with simple yet powerful tools to study the pathogenic mechanisms associated with human disease-causing genes.

Abstract

Editors' choice - Drosophila Collection: In this review and accompanying poster, we highlight the physiological and molecular parallels between fly and human organs that validate the use of Drosophila to study the molecular pathogenesis underlying human diseases.

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Most cited references 118

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Using FlyAtlas to identify better Drosophila melanogaster models of human disease.

Venkateswara Chintapalli, Jing WANG, Julian Dow … (2007)

FlyAtlas, a new online resource, provides the most comprehensive view yet of expression in multiple tissues of Drosophila melanogaster. Meta-analysis of the data shows that a significant fraction of the genome is expressed with great tissue specificity in the adult, demonstrating the need for the functional genomic community to embrace a wide range of functional phenotypes. Well-known developmental genes are often reused in surprising tissues in the adult, suggesting new functions. The homologs of many human genetic disease loci show selective expression in the Drosophila tissues analogous to the affected human tissues, providing a useful filter for potential candidate genes. Additionally, the contributions of each tissue to the whole-fly array signal can be calculated, demonstrating the limitations of whole-organism approaches to functional genomics and allowing modeling of a simple tissue fractionation procedure that should improve detection of weak or tissue-specific signals.

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Mutations in NOTCH1 cause aortic valve disease.

Vidu Garg, Alecia N. Muth, Joshua F Ransom … (2005)

Calcification of the aortic valve is the third leading cause of heart disease in adults. The incidence increases with age, and it is often associated with a bicuspid aortic valve present in 1-2% of the population. Despite the frequency, neither the mechanisms of valve calcification nor the developmental origin of a two, rather than three, leaflet aortic valve is known. Here, we show that mutations in the signalling and transcriptional regulator NOTCH1 cause a spectrum of developmental aortic valve anomalies and severe valve calcification in non-syndromic autosomal-dominant human pedigrees. Consistent with the valve calcification phenotype, Notch1 transcripts were most abundant in the developing aortic valve of mice, and Notch1 repressed the activity of Runx2, a central transcriptional regulator of osteoblast cell fate. The hairy-related family of transcriptional repressors (Hrt), which are activated by Notch1 signalling, physically interacted with Runx2 and repressed Runx2 transcriptional activity independent of histone deacetylase activity. These results suggest that NOTCH1 mutations cause an early developmental defect in the aortic valve and a later de-repression of calcium deposition that causes progressive aortic valve disease.

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High-throughput Ethomics in Large Groups of Drosophila

Kristin Branson, Alice Robie, John F Bender … (2009)

We present a camera-based method for automatically quantifying the individual and social behaviors of fruit flies, Drosophila melanogaster, interacting within a planar arena. Our system includes machine vision algorithms that accurately track many individuals without swapping identities and classification algorithms that detect behaviors. The data may be represented as an ethogram that plots the time course of behaviors exhibited by each fly, or as a vector that concisely captures the statistical properties of all behaviors displayed within a given period. We found that behavioral differences between individuals are consistent over time and are sufficient to accurately predict gender and genotype. In addition, we show that the relative positions of flies during social interactions vary according to gender, genotype, and social environment. We expect that our software, which permits high-throughput screening, will complement existing molecular methods available in Drosophila, facilitating new investigations into the genetic and cellular basis of behavior.

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Author and article information

Journal

Journal ID (nlm-ta): Dis Model Mech

Journal ID (iso-abbrev): Dis Model Mech

Journal ID (publisher-id): DMM

Journal ID (hwp): dmm

Title: Disease Models & Mechanisms

Publisher: The Company of Biologists Ltd

ISSN (Print): 1754-8403

ISSN (Electronic): 1754-8411

Publication date (Print): 1 March 2016

Publication date PMC-release: 1 March 2016

Volume: 9

Issue: 3 , SUBJECT COLLECTION: SPOTLIGHT ON DROSOPHILA: TRANSLATIONAL IMPACT

Pages: 235-244

Affiliations

[1 ]Program in Developmental Biology, Baylor College of Medicine , Houston, TX 77030, USA

[2 ]Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030, USA

[3 ]Department of Neuroscience, Baylor College of Medicine , Houston, TX 77030, USA

[4 ]Howard Hughes Medical Institute, Baylor College of Medicine , Houston, TX 77030, USA

[5 ]Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital , Houston, TX 77030, USA

Author notes

[*]

These authors contributed equally to this work.

[‡ ]Author for correspondence ( hbellen@ 123456bcm.edu )

Article

Publisher ID: DMM023762

DOI: 10.1242/dmm.023762

PMC ID: 4833332

PubMed ID: 26935102

SO-VID: bd032026-6fe1-4707-811b-8054ccb1e95f

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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Funding

Funded by: Friedreich's Ataxia Research Alliance, http://dx.doi.org/10.13039/100002108;

Funded by: Howard Hughes Medical Institute, http://dx.doi.org/10.13039/100000011;

Drosophila tools and assays for the study of human diseases

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Most cited references 118

Using FlyAtlas to identify better Drosophila melanogaster models of human disease.

Mutations in NOTCH1 cause aortic valve disease.

High-throughput Ethomics in Large Groups of Drosophila

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