Consequences of lack of β1 integrin gene expression in mice

Abstract

β1 integrins are cell-surface receptors that mediate cell-cell and cell- matrix interactions. We have generated a null mutation in the gene for the β1 integrin subunit in mice and embryonic stem (ES) cells. Heterozygous mice are indistinguishable from normal littermates. Homozygous null embryos develop normally to the blastocyst stage, implant, and invade the uterine basement membrane but die shortly thereafter. Using β1 integrin-deficient ES cells we have established chimeric embryos and adult mice. Analysis of the chimeric embryos demonstrated the presence of β1 integrin-deficient cells in all germ layers indicating that β1-null cells can differentiate and migrate in a context of normal tissue. When evaluated at embryonic day 9.5 (E9.5), embryos with a β1-null cell contribution below 25% were developing normally, whereas embryos with a contribution above this threshold were distorted and showed abnormal morphogenesis. In adult chimeric mice β1 integrin-deficient cells failed to colonize liver and spleen but were found in all other tissues analyzed at levels from 2%-25%. Immunostaining of chimeric mice showed that in cardiac muscle, there were small, scattered patches of myocytes that were β1-null. In contrast, many myotubes showed some β1-null contribution as a result of fusion between wild-type and mutant myoblasts to form mixed myotubes. The adult chimeric brain contained β1-null cells in all regions analyzed. Also, tissues derived from the neural crest contained β1 integrin- deficient cells indicating that migration of neuronal cells as well as neural crest cells can occur in the absence of β1 integrins.