TARGETED DISRUPTION OF THE CD3-ETA LOCUS CAUSES HIGH LETHALITY IN MICE - MODULATION OF OCT-1 TRANSCRIPTION ON THE OPPOSITE STRAND

CD3 zeta and eta chains are components of the T cell antigen receptor (TCR) complex and are transcribed from a common gene by alternative sp licing. TCR complexes containing the zeta eta dimer have been thought to mediate different functions than complexes containing the zeta(2) d imer. To analyze the role of eta in the development and function of T cells, we generated eta-deficient mice without affecting zeta by gene targeting in embryonic stem cells. Homozygous mutant embryos developed normally. Unexpectedly, however, these mice exhibited high mortality soon after birth for unknown reason(s). Analysis of surviving homozygo us animals revealed that the development and function of T cells were normal in the absence of the eta chain. Recently, the zeta/eta locus w as reported to encode a transcription factor, Oct-1, on the opposite D NA strand. Our targeting strategy resulted in modulation of Oct-1 tran scription-reduction of the authentic Oct-1 mRNA and induction of aberr ant transcripts. Although differences in tissue distribution and DNA b inding capacity of Oct-1 between wild-type and eta-deficient mice were not evident from in situ hybridization and gel shift analysis, the hi gh mortality in the eta-deficient strain may well be due to the distur bance of Oct-1 transcription by the mutation in the zeta/eta locus. Su ch possible complexities have to be taken into account in the interpre tation of gene targeting experiments.