Cardiac performance in the zebrafish<i>breakdance</i>mutant

Kopp, Renate; Schwerte, Thorsten; Pelster, Bernd

doi:10.1242/jeb.01620

Cited by 80 publications

(61 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the present study we confirmed the previously established significant reduction in cardiac output in bre animals (27) and significantly extended the physiological characterization of the mutant with a special focus on hypoxic signaling pathways. Expression array analyses were performed to assess the general impact of a chronically reduced cardiac output.…”

supporting

confidence: 87%

See 1 more Smart Citation

Chronic reduction in cardiac output induces hypoxic signaling in larval zebrafish even at a time when convective oxygen transport is not required

Kopp

Schwerte

Egg

et al. 2010

Physiological Genomics

Self Cite

View full text Add to dashboard Cite

In the present study, the zebrafish breakdance mutant (bre) was used to assess the role of blood flow in development because it has been previously shown that bre larvae have a chronically reduced cardiac output as a result of ventricular contraction following only every second atrial contraction in addition to an atrial bradycardia. We confirmed a 50% reduction compared with control fish and further showed that blood flow in the caudal part of the dorsal aorta decreased by 80%. Associated with these reductions in blood flow were indications of developmental retardation in bre mutants, specifically delayed hatching, reduced cell proliferation, and a transiently decreased growth rate. Surprisingly, an increased red blood cell concentration and an earlier appearance of trunk vessels in bre larvae indicated some compensation to convective oxygen transport, although in previous studies it has been shown that zebrafish larvae at this stage obtain oxygen by bulk diffusion. In bre animals immunohistochemical analyses showed a significant increase in hypoxia inducible factor 1 (HIF)-α protein expression, comparable with wild-type larvae that were raised under hypoxic conditions. Accordingly, the expression of some hif downstream genes was affected. Furthermore, Affymetrix microarray analyses revealed a large number of genes that were differently expressed comparing control and bre larvae, and the number even increased with proceeding development. The results showed that a chronic reduction in blood flow generated hypoxic molecular signals despite partial compensation by increased oxygen carrying capacity and transiently slowed the overall development of zebrafish bre larvae.

show abstract

supporting

confidence: 87%

“…Afterward the larvae were carefully removed from the agarose and returned to a separate incubation tank. Heart images of bre larvae were used for analysis only when they showed the 2:1 rhythm of cardiac contraction (27).…”

Section: Physiological Experimentsmentioning

confidence: 99%

Chronic reduction in cardiac output induces hypoxic signaling in larval zebrafish even at a time when convective oxygen transport is not required

Kopp

Schwerte

Egg

et al. 2010

Physiological Genomics

Self Cite

View full text Add to dashboard Cite

show abstract

“…For example, embryonic and adult heart rates are similar to those of humans (10,11), and the relationship between QT interval and heart rate parallels that of humans (11). Forward-genetic screens using zebrafish have identified many cardiovascular mutants for analysis (12,13), thereby revealing critical pathways in cardiovascular development that parallel those of higher vertebrates (14).…”

mentioning

confidence: 99%

Zebrafish model for human long QT syndrome

Arnaout

Ferrer

Huisken

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

215

212

View full text Add to dashboard Cite

Long QT syndrome (LQTS) is a disorder of ventricular repolarization that predisposes affected individuals to lethal cardiac arrhythmias. To date, an appropriate animal model of inherited LQTS does not exist. The zebrafish is a powerful vertebrate model used to dissect molecular pathways of cardiovascular development and disease. Because fundamental electrical properties of the zebrafish heart are remarkably similar to those of the human heart, the zebrafish may be an appropriate model for studying human inherited arrhythmias. Here we describe the molecular, cellular, and electrophysiological basis of a zebrafish mutant characterized by ventricular asystole. Genetic mapping and direct sequencing identify the affected gene as kcnh2, which encodes the channel responsible for the rapidly activating delayed rectifier K ؉ current (IKr). We show that complete loss of functional IKr in embryonic hearts leads to ventricular cell membrane depolarization, inability to generate action potentials (APs), and disrupted calcium release. A small hyperpolarizing current restores spontaneous APs, implying wildtype function of other ionic currents critical for AP generation. Heterozygous fish manifest overt cellular and electrocardiographic evidence for delayed ventricular repolarization. Our findings provide insight into the pathogenesis of homozygous kcnh2 mutations and expand the use of zebrafish mutants as a model system to study human arrhythmias.cardiac ͉ development ͉ kcnh2 ͉ arrhythmia ͉ electrophysiology A utosomal dominant KCNH2 mutations account for Ϸ45% of mutation-positive long QT syndrome (LQTS) (1, 2). Recessive KCNH2 mutations are rarely reported, implying that most homozygous mutations are embryonic-lethal (3, 4). The cellular mechanisms underlying embryonic lethality are not known. Although LQTS has been extensively characterized in humans, establishing an animal model would be helpful to identify genes that modify phenotypic expressivity or to screen against compounds that cause acquired forms of LQTS. To date, an appropriate animal model of inherited LQTS does not exist. Transgenic strategies and targeted deletion of genes that regulate rapidly activating delayed rectifier K ϩ current (I Kr ) and slow delayed rectifier K ϩ current (I Ks ) in mice fail to produce a significant phenotype (5-7). The mouse heart rate is nearly 10 times faster than that of humans, and thus a distinct cadre of ion channels facilitates ventricular repolarization in mice (5-8).Although the zebrafish heart is two-chambered, its fundamental electrical properties are remarkably similar to those of humans (9). For example, embryonic and adult heart rates are similar to those of humans (10, 11), and the relationship between QT interval and heart rate parallels that of humans (11). Forward-genetic screens using zebrafish have identified many cardiovascular mutants for analysis (12, 13), thereby revealing critical pathways in cardiovascular development that parallel those of higher vertebrates (14). Large clutch size facilitates positional clo...

show abstract

“…This characteristic allows for the study of early development despite severe developmental defects in both heart morphology and physiology without the embryo dying. These traits have allowed models of several human cardiovascular diseases to be developed in zebrafish including dilated cardiomyopathy [5], vascular lipid deposition [6], long QT syndrome [7], aortic coarctation [8], and arrhythmic right ventricular cardiomyopathy [9].…”

Section: General Considerationsmentioning

confidence: 99%

Small Molecule Screening in Zebrafish

Peal

Peterson

Milan

2010

J. of Cardiovasc. Trans. Res.

View full text Add to dashboard Cite

Small molecule screens have become useful tools in ongoing efforts to understand complex biologic systems and disease states. These screens can identify compounds that specifically affect signaling pathways, development, and disease processes. The zebrafish Danio rerio has increasingly been used as a whole organism model in which to perform such functional small molecule screens. Here, we review recent advances in screening approaches that focus on modulation of developmental processes and signaling pathways, along with suppressor screens of disease models. The identification of small molecule targets continues to be a challenge, and several recent approaches to this problem are discussed. The promise of chemical screens in zebrafish to identify novel biologic probes and therapeutic compounds continues to drive this rapidly growing field.

show abstract

Cardiac performance in the zebrafishbreakdancemutant

Cited by 80 publications

References 36 publications

Chronic reduction in cardiac output induces hypoxic signaling in larval zebrafish even at a time when convective oxygen transport is not required

Chronic reduction in cardiac output induces hypoxic signaling in larval zebrafish even at a time when convective oxygen transport is not required

Zebrafish model for human long QT syndrome

Small Molecule Screening in Zebrafish

Contact Info

Product

Resources

About