1. We have described an animal model to induce the histogenesis of squamous metaplasia in the columnar epithelium of the cervix uteri, a condition usually preceding cervical neoplasia. This model is based on dietary retinoid depletion in female mice. This nutritional regimen, the use of specific keratin antibodies and the technique of in situ hybridization have enabled us to identify the gradual appearance of reserve cells in focal and discontinuous distribution patterns within the columnar endocervical epithelium and uterine glands. These reserve cells eventually grow into squamous metaplastic foci, which express keratins normally found in the stratified-squamous epithelium of the cervix uteri. Metaplastic focal lesions eventually replace the entire columnar epithelium. A differentiation-specific expression of the retinoic acid receptors was found, with retinoic acid receptor beta mainly localized in the columnar epithelium and retinoic acid receptor gamma in stratified squamous epithelium. 2. Programmed cell death is a key process in the maintenance of normal tissue growth and differentiation. Transglutaminases are involved in this process and the tissue-type transglutaminase is regulated by retinoic acid in vivo and in cell culture. We found that the oncogenes Ha-ras, N-ras and K-ras transfected into NIH-3T3 cells abrogate the retinoic acid induced stimulation of transglutaminase. Other cytoplasmic oncogenes (B-raf, v-raf and met) had the same effect as ras, whereas transfection of the fos oncogene failed to abrogate the response of the cells to retinoic acid. The data suggest intersecting pathways of retinoic acid and cytoplasmic oncogenes.
