Rationale: 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.

Methods and 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 γ-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.