Dominant-negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo.
Abstract
The receptor tyrosine kinases (RTKs) expressed on the surface of endothelial cells are likely to play key roles in initiating the program of endothelial cell growth during development and subsequent vascularization during wound healing and tumorigenesis. Expression of the Tek RTK during mouse development is restricted primarily to endothelial cells and their progenitors, the angioblasts, suggesting that Tek is a key participant in vasculogenesis. To investigate the role that Tek plays within the endothelial cell lineage, we have disrupted the Tek signaling pathway using two different genetic approaches. First, we constructed transgenic mice expressing a dominant-negative form of the Tek receptor. Second, we created a null allele of the tek gene by homologous recombination in embryonic stem (ES) cells. Transgenic mice expressing dominant-negative alleles of Tek or homozygous for a null allele of the tek locus both died in utero with similar defects in the integrity of their endothelium. By crossing transgenic mice that express the lacZ reporter gene under the transcriptional control of the endothelial cell-specific tek promoter, we found that the extraembryonic and embryonic vasculature was patterned correctly. However, homozygous tek embryos had approximately 30% and 75% fewer endothelial cells at day 8.5 and 9.0, respectively. Homozygous null embryos also displayed abnormalities in heart development, consistent with the conclusion that Tek is necessary for endocardial/myocardial interactions during development. On the basis of the analysis of mice carrying either dominant-negative or null mutations of the tek gene, these observations demonstrate that the Tek signaling pathway plays a critical role in the differentiation, proliferation, and survival of endothelial cells in the mouse embryo.
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From Adipose tissue remodeling and obesity (2011) · cites this paper as [86]
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- Authors
- Dumont, D. J., Gradwohl, G., Fong, G. H., Puri, M. C., Gertsenstein, M., Auerbach, A., & Breitman, M. L.
- Affiliations
- Mount Sinai Hospital (CA)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 1994-08-15
- Volume
- 8
- Issue
- 16
- Pages
- 1897-1909
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- OpenAlex
- W2140459348
- Cited by
- 985
- References
- 42
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 8 · 2023: 12 · 2022: 18 · 2021: 18 · 2020: 21 · 2019: 22 · 2018: 16 · 2017: 21 · 2016: 16 · 2015: 18 · 2014: 26 · 2013: 27 · 2012: 29
- Type
- posted content
- Language
- en
- Open access
- closed
- Locations
- Genes & Development (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Medical Research Council
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Zebrafish Biomedical Research Applications
- Keywords
- vasculogenesis, endothelial cells, angioblasts, dominant negative mutation, null alleles, endothelial differentiation, endothelial cell proliferation, endothelial cell survival, heart development, embryonic vasculature, mouse embryo
- MeSH terms
- Animals, Base Sequence, Endothelium, Vascular, Female, Genes, Dominant, Heart, Hemorrhage, Homozygote, Male, Mice, Transgenic, Molecular Sequence Data, Pregnancy, Proteins, Signal Transduction, DNA Primers, DNA, Complementary, Receptor Protein-Tyrosine Kinases, Receptor, TIE-2, Mice
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