Gene deletion screen for cardiomyopathy in adult Drosophila identifies a new notch ligand.
BACKGROUND
Drosophila has been recognized as a model to study human cardiac diseases.


OBJECTIVE
Despite these findings, and the wealth of tools that are available to the fly community, forward genetic screens for adult heart phenotypes have been rarely performed because of the difficulty in accurately measuring cardiac function in adult Drosophila.


RESULTS
Using optical coherence tomography to obtain real-time analysis of cardiac function in awake Drosophila, we performed a genomic deficiency screen in adult flies. Based on multiple complementary approaches, we identified CG31665 as a novel gene causing dilated cardiomyopathy. CG31665, which we name weary (wry), has structural similarities to members of the Notch family. Using cell aggregation assays and gamma-secretase inhibitors we show that Wry is a novel Notch ligand that can mediate cellular adhesion with Notch expressing cells and transactivates Notch to promote signaling and nuclear transcription. Importantly, Wry lacks a DSL (Delta-Serrate-Lag) domain that is common feature to the other Drosophila Notch ligands. We further show that Notch signaling is critically important for the maintenance of normal heart function of the adult fly.


CONCLUSIONS
In conclusion, we identify a previously unknown Notch ligand in Drosophila that when deleted causes cardiomyopathy. Our study suggests that Notch signaling components may be a therapeutic target for dilated cardiomyopathy.
Kim
Il-Man
IM
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Wolf
Matthew J
MJ
Rockman
Howard A
HA
D000818:Animals; D030801:Animals, Genetically Modified; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002448:Cell Adhesion; D002449:Cell Aggregation; D002460:Cell Line; D004251:DNA Transposable Elements; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D005838:Genotype; D008024:Ligands; D010641:Phenotype; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D051880:Receptors, Notch / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D041623:Tomography, Optical Coherence; D015533:Transcriptional Activation; D014162:Transfection
D004251:DNA Transposable Elements; D029721:Drosophila Proteins; D008024:Ligands; C497759:N protein, Drosophila; D051880:Receptors, Notch; D011994:Recombinant Proteins