THE E1A TRANSCRIPTIONAL CONTROL REGION IS EFFICIENTLY ACTIVATED IN PROLIFERATING TISSUES OF TRANSGENIC MICE

To study the in vivo regulation of the adenovirus E1A transcriptional regulatory region in transgenic mice, we have constructed two hybrid g enes in which the viral control element regulates the expression of th e CAT and the lacZ reporter gene. The fusion constructs were introduce d into the mouse germline. The expression of the transgenes were monit ored during embryogenesis and during postnatal development as web as i n adult organs. We show that the E1A regulatory region is recognized a nd activated in undifferentiated cells during early embryonic cleavage , in the morula, in the inner cell mass and in the trophectoderm of th e blastocyst. Transcription initiation at the E1A promoter leads to hi gher marker gene expression in proliferative centers in postimplantati on embryos at the beginning of the neural tube closure. Analysing mark er gene expression during postnatal development, a correlation of tran scriptional activity of the E1A regulatory region and cell proliferati on could be demonstrated. The expression profile of the transgene in d ifferent adult organs parallels with DNA synthesis. Marker gene expres sion was high in cells of organs known to have a high mitotic rate, su ch as the intestine, the stomach, the skin and the bone marrow, wherea s little activity of the E1A control region was observed in the post-p roliferative brain. These results are consistent with the finding that activation of the viral cis-regulating elements dramatically increase d in the kidney after mitotic stimulation by folic acid. These observa tions strongly suggests a cell cycle regulated expression from the E1A enhancer/promoter in the absence of the E1A autoregulatory proteins i n the living animal.