Affecting Rhomboid-3 function causes a dilated heart in adult Drosophila.
Affecting Rhomboid-3 function causes a dilated heart in adult Drosophila.
复制标题
DOI：
10.1371/journal.pgen.1000969
复制
发表时间：
2010-05-27
期刊：
影响因子：
4.5
通讯作者：
Wolf MJ
中科院分区：
文献类型：
--
作者：
Yu L;Lee T;Lin N;Wolf MJ
Drosophila is a well recognized model of several human diseases, and recent investigations have demonstrated that Drosophila can be used as a model of human heart failure. Previously, we described that optical coherence tomography (OCT) can be used to rapidly examine the cardiac function in adult, awake flies. This technique provides images that are similar to echocardiography in humans, and therefore we postulated that this approach could be combined with the vast resources that are available in the fly community to identify new mutants that have abnormal heart function, a hallmark of certain cardiovascular diseases. Using OCT to examine the cardiac function in adult Drosophila from a set of molecularly-defined genomic deficiencies from the DrosDel and Exelixis collections, we identified an abnormally enlarged cardiac chamber in a series of deficiency mutants spanning the rhomboid 3 locus. Rhomboid 3 is a member of a highly conserved family of intramembrane serine proteases and processes Spitz, an epidermal growth factor (EGF)–like ligand. Using multiple approaches based on the examination of deficiency stocks, a series of mutants in the rhomboid-Spitz–EGF receptor pathway, and cardiac-specific transgenic rescue or dominant-negative repression of EGFR, we demonstrate that rhomboid 3 mediated activation of the EGF receptor pathway is necessary for proper adult cardiac function. The importance of EGF receptor signaling in the adult Drosophila heart underscores the concept that evolutionarily conserved signaling mechanisms are required to maintain normal myocardial function. Interestingly, prior work showing the inhibition of ErbB2, a member of the EGF receptor family, in transgenic knock-out mice or individuals that received herceptin chemotherapy is associated with the development of dilated cardiomyopathy. Our results, in conjunction with the demonstration that altered ErbB2 signaling underlies certain forms of mammalian cardiomyopathy, suggest that an evolutionarily conserved signaling mechanism may be necessary to maintain post-developmental cardiac function. Heart failure is a common cardiovascular disease that is characterized by problems with the ability of the heart muscle to contract, called impaired systolic function, and an enlarged heart chamber. Model systems of human heart failure are necessary to facilitate the screening and identification of genes and genetic variations that either cause or influence the development and progression of this disease. To better understand these genes, we conducted a genetic screen employing molecularly defined deletions throughout the genome of the adult fruit fly, Drosophila melanogaster. We used an optical coherence tomography imaging technique that provided images similar to echocardiography in humans to measure the cardiac function in adult flies. We identified mutants in members of the rhomboid protease family and epidermal growth factor receptor that cause an enlarged cardiac chamber. Interestingly, abnormalities in the function of members of the epidermal growth factor receptor family in humans that undergo certain chemotherapies are associated with the development of dilated cardiomyopathy and heart failure. Our results suggest that epidermal growth factor receptor signaling may be an evolutionarily conserved pathway that is necessary to maintain normal adult cardiac function.
登录
查看更多内容
影响因子：
2.7
作者：
Brown, Katherine E.;Kerr, Martin;Freeman, Matthew
通讯作者：
Freeman, Matthew
影响因子：
64.5
作者：
Freeman, M
通讯作者：
Freeman, M
DOI：
10.1126/science.1182228
发表时间：
2010-03-05
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Lee JH;Budanov AV;Park EJ;Birse R;Kim TE;Perkins GA;Ocorr K;Ellisman MH;Bodmer R;Bier E;Karin M
通讯作者：
Karin M
影响因子：
4.6
作者：
Brown, KE;Freeman, M
通讯作者：
Freeman, M
影响因子：
2.7
作者：
McDonald, Jocelyn A.;Pinheiro, Elaine M.;Montell, Denise J.
通讯作者：
Montell, Denise J.