A TARGETED MUTATION IN THE MOUSE E-CADHERIN GENE RESULTS IN DEFECTIVEPREIMPLANTATION DEVELOPMENT

The Ca2+-dependent cell adhesion molecule E-cadherin functions in the establishment and maintenance of epithelial cell morphology during emb ryogenesis and adulthood. Downregulation or complete shut-down of E-ca dherin expression and mutation of the gene are observed during the pro gression of tumors of epithelial origin (carcinomas) and correlate wit h the metastatic potential. We have introduced a targeted mutation int o the E-cadherin gene by homologous recombination in mouse embryonic s tem cells. The mutation removes E-cadherin sequences essential for Ca2 + binding and for adhesive function. These embryonic stem cells were u sed to generate mice carrying the mutation. Heterozygous mutant animal s appear normal and are fertile. However, the homozygous mutation is n ot compatible with life: E-cadherin -/- embryos show severe abnormalit ies before implantation. Particularly, the adhesive cells of the morul a dissociate shortly after compaction has occurred, and their morpholo gical polarization is then destroyed. Interestingly, the blastomers ar e still able to form desmosomes and tight junctions at sites of distor ted cell-cell contact. Thus, maternal E-cadherin suffices for initial compaction of the morula but not for further preimplantation developme nt to occur.