Journal article
Early Myocardial Function Affects Endocardial Cushion Development in Zebrafish
PLoS biology, Vol.2(5), pp.673-681
05/2004
DOI: 10.1371/journal.pbio.0020129
PMID: 15138499
Abstract
Function of the heart begins long before its formation is complete. Analyses in mouse and zebrafish have shown that myocardial function is not required for early steps of organogenesis, such as formation of the heart tube or chamber specification. However, whether myocardial function is required for later steps of cardiac development, such as endocardial cushion (EC) formation, has not been established. Recent technical advances and approaches have provided novel inroads toward the study of organogenesis, allowing us to examine the effects of both genetic and pharmacological perturbations of myocardial function on EC formation in zebrafish. To address whether myocardial function is required for EC formation, we examined s
ilent heart (sih
−/−
)
embryos, which lack a heartbeat due to mutation of
cardiac troponin T
(
tnnt2
), and observed that atrioventricular (AV) ECs do not form. Likewise, we determined that cushion formation is blocked in
cardiofunk (cfk
−/−
)
embryos, which exhibit cardiac dilation and no early blood flow. In order to further analyze the heart defects in
cfk
−/−
embryos, we positionally cloned
cfk
and show that it encodes a novel sarcomeric actin expressed in the embryonic myocardium. The Cfk
s11
variant exhibits a change in a universally conserved residue (R177H). We show that in yeast this mutation negatively affects actin polymerization. Because the lack of cushion formation in
sih-
and
cfk-
mutant embryos could be due to reduced myocardial function and/or lack of blood flow, we approached this question pharmacologically and provide evidence that reduction in myocardial function is primarily responsible for the defect in cushion development. Our data demonstrate that early myocardial function is required for later steps of organogenesis and suggest that myocardial function, not endothelial shear stress, is the major epigenetic factor controlling late heart development. Based on these observations, we postulate that defects in cardiac morphogenesis may be secondary to mutations affecting early myocardial function, and that, in humans, mutations affecting embryonic myocardial function may be responsible for structural congenital heart disease.
Cardiac anomolies can result from very early defects in heart development. In zebrafish, such defects have been shown to be caused by a new gene called
cardiofunk
Details
- Title: Subtitle
- Early Myocardial Function Affects Endocardial Cushion Development in Zebrafish
- Creators
- Thomas Bartman - Department of Biochemistry and Biophysics, University of CaliforniaEmily C Walsh - Department of Biochemistry and Biophysics, University of CaliforniaKuo-Kuang Wen - Department of Biochemistry, University of Iowa College of MedicineMelissa McKane - Department of Biochemistry, University of Iowa College of MedicineJihui Ren - Department of Biochemistry, University of Iowa College of MedicineJonathan Alexander - Department of Biochemistry and Biophysics, University of CaliforniaPeter A Rubenstein - Department of Biochemistry, University of Iowa College of MedicineDidier Y. R Stainier - Department of Biochemistry and Biophysics, University of California
- Resource Type
- Journal article
- Publication Details
- PLoS biology, Vol.2(5), pp.673-681
- DOI
- 10.1371/journal.pbio.0020129
- PMID
- 15138499
- NLM abbreviation
- PLoS Biol
- ISSN
- 1544-9173
- eISSN
- 1545-7885
- Publisher
- Public Library of Science; San Francisco, USA
- Alternative title
- Myocardial Function and Cushion Development
- Language
- English
- Date published
- 05/2004
- Academic Unit
- Stead Family Department of Pediatrics; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984024559502771
Metrics
16 Record Views