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To study how the oncogenic process may involve effects on differentiation, we overexpressed an immortalizing oncogene in a developing tissue in transgenic mice. By use of a gene fusion of the alpha A-crystallin promoter to the viral immortalizing oncogene, polyoma large T antigen (PyLT), we created transgenic mice that express PyLT specifically in ocular lens. Expression of large T antigen during embryonic development led to a perturbation in lens development, specifically, an interference with the normal program of fiber cell differentiation. This resulted in microphthalmia, which persisted throughout the life of the animal. Histological analysis revealed impairment of cell elongation, denucleation, and mitotic senescence in both primary and secondary fiber cell differentiation. Strikingly, there was no evidence for hyperplasia or for tumor development in vivo, unlike the consequences of many immortalizing oncogenes on tissues in other transgenic mice. In vitro, however, the developmentally perturbed cells derived from the transgenic lens showed high proliferative capacity. Our results suggest that a primary effect of aberrant expression of an immortalizing gene is an interference with normal tissue development; however, this interference may not necessarily induce proliferation or lead to tumor formation.

Perturbed development of the mouse lens by polyomavirus large T antigen does not lead to tumor formation.