CELL LINEAGE-SPECIFIC AND DIFFERENTIATION-DEPENDENT PATTERNS OF CCAATENHANCER-BINDING PROTEIN-ALPHA EXPRESSION IN THE GUT EPITHELIUM OF NORMAL AND TRANSGENIC MICE

The proliferation and differentiation programs of gut epithelial cells we expressed rapidly and perpetually along an anatomically well defin ed pathway. The mouse intestine thus provides an excellent in vivo mod el system to define the contributions of CCAAT enhancer binding protei n alpha (C/EBPalpha) and related bZIP proteins to these processes. Imm unocytochemical studies revealed that C/EBPalpha is produced in villus -associated enterocytes located in the duodenum and jejunum of adult m ice. The protein is located in the cytoplasmic and nuclear compartment s of these cells. C/EBPalpha is not detectable in proliferating and no nproliferating epithelial cells situated in small intestinal crypts no r is it evident in any gut epithelial cell lineage located in the ileu m and colon. The related C/EBPbeta and C/EBPdelta proteins are not det ectable by sensitive immunocytochemical methods in epithelial cells di stributed along the duodenal-to-colonic axis. Developmental surveys in dicate that C/EBPalpha is confined to postmitotic, villus-associated e pithelial cells during conversion of the polyclonal intervillus epithe lium to monoclonal crypts. Analyses of intestinal isografts reveal tha t these developmental stage-specific, lineage-specific, differentiatio n-dependent, and regional patterns of C/EBPalpha expression can be est ablished and maintained in the absence of exposure to luminal contents . Transgenic mice containing nucleotides -1178 to +28 of the rat intes tinal fatty acid binding protein gene (I-FABp-1178 to +28) linked to t he simian virus 40 large tumor antigen (T antigen) gene express T anti gen in villus-associated enterocytes. This results in reentry of enter ocytes into the cell cycle and a silencing of C/EBPalpha expression wi thout an apparent effect on the accumulation of several markers of thi s lineage's terminal differentiation program or on gut morphogenesis. These findings indicate that there is a relationship between expressio n of C/EBPalpha in enterocytes and their exit from the cell cycle and suggest that I-FABP-1178 to +28/simian virus 40 T antigen transgenic m ice could provide a screening assay for examining the role of C/EBPalp ha in regulating the activity of genes known to be transcribed during differentiation of this gut epithelial cell lineage.