Cdc42 and Tinman march to the same beat
نویسنده
چکیده
D rosophila may be small, but you can’t accuse them of lacking heart. Unless they’re missing the transcription factor Tinman, that is, in which case they fail to form a heart during embryogenesis (1, 2) or, if tinman is deleted later in development, they fail to maintain adult cardiac function (3). Qian et al. now reveal how Tinman works in conjunction with the small GTPase Cdc42 to regulate the heart in both fl ies and mice (4). Tinman lies at the top of a complex hierarchical network that makes and maintains the heart. Much of this network—including Tinman itself—is conserved in mammals. “So we can use Drosophila to learn about the fundamental genetic mechanisms that are important for the development and function of the heart,” says Rolf Bodmer, from the Sanford-Burnham Medical Research Institute in La Jolla, CA. To discover new genes that work with tinman to maintain adult heart function, Bodmer and colleagues performed a genetic screen for mutations that cause heart failure in fl ies heterozygous for a deletion of tinman (4). Using this approach, Qian et al. found a genetic interaction between tinman and Cdc42. Whereas fl ies lacking one copy of either tinman or Cdc42 were healthy, animals lacking one copy of both genes had multiple heart defects. “The fl ies’ hearts didn’t beat as regularly, and the heart myofi brils weren’t arranged in a parallel, organized fashion,” Bodmer recounts. Expressing a dominant-negative version of Cdc42 in cardiac tissue produced similar effects. The heart arrhythmias in tinman/Cdc42 double heterozygotes prompted Qian et al. to investigate the expression in these fl ies of several ion channels that regulate heart beat patterns. The expression of two potassium channels—dSUR and slowpoke—was down-regulated in double-heterozygous fl ies, and in vitro experiments revealed that Tinman and Cdc42 act together genetically to promote dSUR expression by regulating its enhancer element. Furthermore, flies lacking one copy of Cdc42 and one copy of either dSUR or slowpoke also had irregular heartbeats and disorganized myofi brils. Complete loss of either Cdc42 or Nkx2-5 (the mammalian homologue of tinman) causes heart defects in mice (5, 6). “So we wanted to see if the combination of Tinman and Cdc42 also affected mouse heart function,” Bodmer explains. Qian et al. found that the loss of one copy of each gene in the mouse, as in the fl y, compromised cardiac contraction and rhythmicity, similar to double-heterozygous fl ies. “However, we didn’t see any aberrations in myofi bril organization in the mice,” Bodmer says. Therefore, although the precise phenotypes differ, Cdc42 and Tinman/Nkx2-5 genetically interact in both mouse and fl y hearts. But what is the nature of this interaction? Qian et al. found that Nkx2-5 inhibited the expression of a microRNA, miR-1, that targets Cdc42 mRNA both in vitro and in mice. miR-1 appears to serve as an intermediate between Tinman and Cdc42 in fl ies as well. Drosophila overexpressing miR-1 in their hearts had decreased Cdc42 and slowpoke levels as well as increased arrhythmias. Mutations in the human homologue of Nkx2-5 are associated with a variety of cardiomyopathies (7), suggesting that Cdc42 may also infl uence human heart disease. “Drosophila genetics is a unique way of identifying polygenic interactions that might aggravate a disease,” Bodmer says. Qian et al.’s collaborators performed a small-scale screen of human samples and found one congenital heart disease patient with a mutated version of Cdc42 not found in control samples. Bodmer now wants to examine families carrying mutations in Nkx2-5 to see whether they have different variants of Cdc42 that could explain differences in the severity of their cardiomyopathies. “We’d also like to look for more genes that interact with tinman or with other factors that we know are important for the heart,” Bodmer says.
منابع مشابه
Tinman/Nkx2-5 acts via miR-1 and upstream of Cdc42 to regulate heart function across species
Unraveling the gene regulatory networks that govern development and function of the mammalian heart is critical for the rational design of therapeutic interventions in human heart disease. Using the Drosophila heart as a platform for identifying novel gene interactions leading to heart disease, we found that the Rho-GTPase Cdc42 cooperates with the cardiac transcription factor Tinman/Nkx2-5. Co...
متن کاملStudy of Cisplatin effects in comparison with Curcumin on Cdc42 gene expression in human Calu-6 lung carcinoma cell line
Lung carcinoma is the second most common type of cancer. Inefficiency of the current treatments and the undesirable side effects of chemotherapy drugs made the know-how of the treatment important. The purpose of this study is to investigate the synergic effect of curcumin and Cisplatin in comparison with the sole application of each treatment on Calu-6 cell line, an epithelial cell line of huma...
متن کاملCdc42 and formin activity control non-muscle myosin dynamics during Drosophila heart morphogenesis
During heart formation, a network of transcription factors and signaling pathways guide cardiac cell fate and differentiation, but the genetic mechanisms orchestrating heart assembly and lumen formation remain unclear. Here, we show that the small GTPase Cdc42 is essential for Drosophila melanogaster heart morphogenesis and lumen formation. Cdc42 genetically interacts with the cardiogenic trans...
متن کاملProbing the polygenic basis of cardiomyopathies in Drosophila
In trying to understand the causes for congenital heart disease and cardiomyopathies, it is difficult to study polygenic interactions that contribute to the severity of the disease, which is in part due to genetic complexity and generation time of higher organisms that hinder efficient screening for modifiers of primary causes of heart disease. The adult Drosophila heart has recently been estab...
متن کاملA role for the COUP-TF-related gene seven-up in the diversification of cardioblast identities in the dorsal vessel of Drosophila
The Drosophila gene tinman is essential for dorsal vessel (heart) formation and is structurally and functionally conserved in vertebrates. In the mature embryonic dorsal vessel, tinman is expressed in four of the six pairs of cardioblasts in each segment. We provide evidence that seven-up, which is homologous to the vertebrate COUP-TF transcription factor and is expressed in the non-Tinman-expr...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
دوره 193 شماره
صفحات -
تاریخ انتشار 2011