Transgenes encoding mutant simian virus 40 large T antigens unmask phenotypic and functional constraints in thymic epithelial cells.
Transgenes encoding simian virus 40 (SV40) T antigen (Tag) can cause hyperplastic or tumorigenic lesions of desired but also of unforeseen cellular origin. Unexpectedly the human growth hormone-releasing factor (GRF) gene promoter directs expression of SV40 Tag specifically in thymic epithelial (TE) cells. Expression starts in the neonate, in which GRF-Tag+ cells display strict numerical and spatial constraints. Tag supersedes mechanisms that constrain these features and GRF-Tag mice develop thymic hyperplasia. To characterize GRF-Tag+ TE cells and their putative normal counterparts we compared phenotypic and functional effects caused by transgenes encoding mutant large T antigens. This strategy is applicable to any situation in which T antigen is used to alter development. One large Tag mutant (K1 + 5080) does not cause thymic hyperplasia. GRF-Tag (K1 + 5080)+ TE cells display strict temporal and spatial constraints throughout life. TE cells expressing other mutant large T antigens that cause thymic hyperplasia do not obey these rules and reveal that phenotypically distinct GRF-Tag+ TE-cell stages exist in vivo. Analysis of conditional immortal GRF-Tag(tsA58)+ TE cells expressing a temperature-sensitive large Tag shows that large Tag blocks differentiation in these cells. Phenotype and functions in these cells are regulated by cellular differentiation and interleukin 4 (IL-4).
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000032:analysis / Q000235:genetics*; D002454:Cell Differentiation; D004847:Epithelial Cells; D013007:Growth Hormone-Releasing Hormone / Q000235:genetics; D015847:Interleukin-4 / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen / Q000235:genetics; D013539:Simian virus 40 / Q000276:immunology*; D013696:Temperature; D013950:Thymus Gland / Q000166:cytology*
D000952:Antigens, Polyomavirus Transforming; D011518:Proto-Oncogene Proteins; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen; D015847:Interleukin-4; D016173:Macrophage Colony-Stimulating Factor; D013007:Growth Hormone-Releasing Hormone; D019009:Proto-Oncogene Proteins c-kit