flies as a model for the study of human disease rapid forward genetics – isolate mutants through...
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Flies as a model for the study of human disease
Rapid forward genetics – isolate mutants throughtransposons or chemical mutagenesis
Rapid construction of transgenic models of human disease
Well established easy systems to drive knockdown/knockout or over expression of gene expression in tissue ortemporal specific patterns
Rapid determination of the molecular basis ofdisease mechanisms
Able to rapidly identify modifier/bypass gene pathways viagenetic screens for enhancersor suppressors of phenotypes
Easy to culture cell lines – very-easy to dsRNA treat genes of interest
GAL4 Tissue specific promoter
X
Transgene UAS OFF
ON
The progeny of this mating will express the transgene in cells also expressing GAL4
GAL4 is a transcriptional activator protein from yeast
The upstream activating sequence is the GAL4 target
GAL4 Tissue specific promoter Transgene UAS
The fly GAL4/UAS binary transgenic expression system
Embryonic Brain Development
Hartenstein - Atlas of Drosophila Development (1993) Cold Spring Harbour Laboratory Press
Larval/Pupal Brain Development
Hartenstein - Atlas of Drosophila Development (1993) Cold Spring Harbour Laboratory Press
The fly fat body is analogues to adipose tissue, the liver and the haematopoietic system in mammals.
Hotamisilgil (2006) Inflammation and metabolic disorders Nature 444, 860-867
Leopold & Perrimon (2007) Drosophila and the genetics of the internal milieu Nature 450, 186-188
Drosophila oenocytes are analogous to mammalian
hepatocytes
Pandley and Nichols (2011) Human Disease Models in Drosophila melanogaster and the Role of the Fly in Therapeutic Drug Discovery Pharmacological Reviews 63(2)411-436
Testing drug candidates in flies
Throughput
A ‘visible’ screen for peroxisome function in Drosophila eyes
ey – eyeless:GAL4
GMR– Glass Multiple Reporter:GAL4
High throughput screening
dsRNA library covering 96% of the Drosophila genome
High Throughput screening