Gene deletion screen for cardiomyopathy in adult drosophila identifies a new notch ligand

Il Man Kim, Matthew J. Wolf, Howard A. Rockman

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1233-1243
Number of pages11
JournalCirculation research
Volume106
Issue number7
DOIs
StatePublished - Apr 1 2010
Externally publishedYes

Keywords

  • Cardiomyopathy gene
  • Drosophila
  • Heart failure
  • Notch signaling
  • Optical coherence tomography

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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