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Creation and characterization of E-selectin- and VCAM-1-deficient mice
L Kwee1, D K Burns, J M Rumberger
1Roche Research Center, Department of Biotechnology, Hoffman-La Roche Inc., Nutley, NJ 07110-1199, USA.
Abstract:
A variety of adhesion molecules have been identified which mediate the interaction of leukocytes with endothelial cells. In order to define the role of individual molecules in inflammation we have produced lines of mice which are deficient in the synthesis of specific adhesion molecules. Null mutations were introduced into the genes encoding E-selectin or vascular cell adhesion molecule-1 (VCAM-1) in embryonic stem cells and these cells were used to produce lines of mice carrying the mutation. E-selectin-deficient mice were viable and exhibited no developmental defects. The roles of E- and P-selectin in the influx of neutrophils were examined using these mice. The data suggest that the two selectins are functionally redundant in mediating neutrophil emigration in a model of chemically induced peritonitis. VCAM-1-deficient mice are not viable. Analysis of VCAM-1 gene expression in wild-type embryos and phenotypic analysis of VCAM-1 -/- embryos suggests that VCAM-1 is required for development of the extraembryonic circulatory system and the embryonic heart.
Insights
Researchers created mice lacking specific adhesion molecules to study inflammation. E-selectin deficiency showed selectins are redundant for neutrophil migration, while VCAM-1 deficiency proved lethal, highlighting its crucial developmental role.
Area of Science:
- Immunology
- Developmental Biology
Background:
- Leukocyte-endothelial cell interactions are crucial in inflammation.
- Adhesion molecules mediate these interactions, but their specific roles require investigation.
Purpose of the Study:
- To elucidate the distinct roles of E-selectin and vascular cell adhesion molecule-1 (VCAM-1) in inflammatory processes.
- To generate genetically modified mouse models for studying adhesion molecule function.
Main Methods:
- Generation of embryonic stem cells with null mutations in E-selectin and VCAM-1 genes.
- Production of genetically deficient mouse lines.
- Phenotypic analysis of mutant mice, including assessment of neutrophil influx and embryonic development.
Main Results:
- E-selectin-deficient mice were viable and showed no developmental abnormalities.
- E-selectin and P-selectin appear functionally redundant in mediating neutrophil emigration during chemically induced peritonitis.
- VCAM-1-deficient mice were non-viable, indicating a critical role in embryonic development.
Conclusions:
- E-selectin and P-selectin exhibit functional redundancy in neutrophil recruitment.
- VCAM-1 is essential for the development of the extraembryonic circulatory system and the embryonic heart.