Cited by 70Zebrafish Biomedical Research ApplicationsCongenital heart defects researchDevelopmental Biology and Gene Regulation

Inhibition of zebrafish epidermal growth factor receptor activity results in cardiovascular defects

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Goishi, Katsutoshi, Lee, Percy, Davidson, Alan J, Nishi, Eiichiro, Zon, Leonard I, Klagsbrun, Michael·2003·Mechanisms of Development

Abstract

The physiological role of any of the epidermal growth factor (EGF) receptor tyrosine kinases has yet to be determined in zebrafish. We isolated a zebrafish homologue of EGFR (egfr) that shows a 63% amino acid overall identity to human EGFR but with 90% amino acid identity in the kinase domain. Whole mount in situ hybridization showed ubiquitous distribution of egfr transcripts during gastrulation, somitogenesis and later stages. When expressed in Chinese hamster ovary cells, zebrafish Egfr was a functional receptor that responded to EGF by receptor tyrosine phosphorylation and activation of MAP kinase. The function of zebrafish Egfr in vivo was determined by inhibiting its activity using EGFR kinase inhibitors and antisense morpholinos (MO), which inhibited Egfr kinase activity and translation of egfr messenger RNA into protein, respectively. The zebrafish is a particularly excellent model for studying cardiovascular development because zebrafish are transparent allowing direct visualization of the heart and circulation in the blood vessels. Inhibition of zebrafish Egfr activity in vivo impeded blood flow via the outflow tract into the aorta and impeded circulation in the axial and intersegmental vessels by 80 h post-fertilization. Analysis of the heart showed that the heart chambers and pericardial sacs were dilated and the outflow tracts were narrowed. Together these results suggested that zebrafish Egfr has a cardiovascular function in the developing zebrafish that is required for normal circulation.

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  1. Westerfield, M., 1995. The Zebrafish Book, Unuversity of Oregon Press, Eugene.

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Authors
Goishi, K., Lee, P., Davidson, A. J., Nishi, E., Zon, L. I., & Klagsbrun, M.
Affiliations
  • Asahikawa Medical College Hospital (JP)
  • Boston Children's Hospital (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
Klagsbrun, Michael
Venue
Mechanisms of Development
Publisher
Elsevier BV
Published
2003-07
Volume
120
Issue
7
Pages
811-822
ISSN
0925-4773 (ISSN-L)
OpenAlex
W2059513313
Cited by
70
References
43
Citations by year
2024: 1 · 2023: 2 · 2022: 1 · 2021: 4 · 2020: 1 · 2019: 4 · 2018: 5 · 2017: 2 · 2016: 6 · 2015: 3 · 2014: 2 · 2013: 5 · 2012: 4
FWCI
1.46
Type
journal article
Language
en
Open access
Locations
  • Mechanisms of Development (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Institutes of Health (DK49216)
  • National Heart, Lung, and Blood Institute (HL 48801, R01HL048801)
  • National Cancer Institute (CA-45448, CA47397)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK49216)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Zebrafish Biomedical Research Applications
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
epidermal growth factor receptor, zebrafish, cardiovascular development, EGFR kinase inhibitors, morpholino antisense, heart development, outflow tract, blood circulation, MAPK signaling, receptor tyrosine phosphorylation
MeSH terms
Amino Acid Sequence, Animals, Humans, Molecular Sequence Data, Pyrimidines, Pyrroles, Quinazolines, Zebrafish, Cardiovascular Abnormalities, Tyrphostins, Rats, ErbB Receptors

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