Targeted disruption of the CD3_η locus causes high lethality in mice: Modulation of Oct-1 transcription on the opposite strand

CD3ζ and η chains are components of the T cell antigen receptor (TCR) complex and are transcribed from a common gene by alternative splicing. TCR complexes containing the ζη dimer have been thought to mediate different functions than complexes containing the ζ₂ dimer. To analyze the role of η in the development and function of T cells, we generated η-deficient mice without affecting ζ 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 homozygous animals revealed that the development and function of T cells were normal in the absence of the η chain. Recently, the ζ/η locus was reported to encode a transcription factor, Oct-1, on the opposite DNA strand. Our targeting strategy resulted in modulation of Oct-1 transcription - reduction of the authentic Oct-1 mRNA and induction of aberrant transcripts. Although differences in tissue distribution and DNA binding capacity of Oct-1 between wild-type and η-deficient mice were not evident from in situ hybridization and gel shift analysis, the high mortality in the η-deficient strain may well be due to the disturbance of Oct-1 transcription by the mutation in the ζ/η locus. Such possible complexities have to be taken into account in the interpretation of gene targeting experiments.