Gene deletion screen for cardiomyopathy in adult Drosophila identifies a new notch ligand.
Gene deletion screen for cardiomyopathy in adult Drosophila identifies a new notch ligand.
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DOI：
10.1161/circresaha.109.213785
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发表时间：
2010-04-16
影响因子：
20.1
通讯作者：
Rockman HA
中科院分区：
文献类型：
--
作者：
Kim IM;Wolf MJ;Rockman HA
果蝇已被公认为研究人类心脏疾病的模型。尽管有这些发现，和丰富的工具，可供苍蝇社区，正向遗传筛选成人心脏表型已很少进行，由于难以准确测量心脏功能的成年果蝇。使用光学相干断层扫描获得清醒果蝇心脏功能的实时分析，我们在成年果蝇中进行了基因组缺陷筛选。基于多种互补的方法，我们确定CG 31665作为一个新的基因引起扩张型心肌病。CG 31665，我们称之为weary（wry），与Notch家族的成员具有结构相似性。使用细胞聚集测定和γ-分泌酶抑制剂，我们表明Wry是一种新型Notch配体，其可以介导与Notch表达细胞的细胞粘附，并反式激活Notch以促进信号传导和核转录。重要的是，Wry缺乏DSL（Delta-Serrate-Lag）结构域，这是其他果蝇Notch配体的共同特征。我们进一步表明，Notch信号是至关重要的维持正常的心脏功能的成年苍蝇。总之，我们确定了一个以前未知的Notch配体在果蝇，当删除导致心肌病。我们的研究表明，Notch信号通路可能是扩张型心肌病的治疗靶点。
Drosophila has been recognized as a model to study human cardiac diseases. 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 due to the difficulty in accurately measuring cardiac function in adult Drosophila. 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. 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.