Conditional expression of the ErbB2 oncogene elicits reversible hyperplasia in stratified epithelia and up-regulation of TGF alpha expression in transgenic mice

The ErbB2 receptor tyrosine kinase (RTK) is expressed in basal cells of squ amous epithelia and the outer root sheath of hair follicles. We previously showed that constitutive expression of activated ErbB2 directed to these si tes in the skin by the keratin 14 (K14) promoter produces prominent hair fo llicle abnormalities and striking skin hyperplasia in transgenic mice. Howe ver, perinatal lethality precluded the establishment of a transgenic line f or analysis of ErbB2 function in adult animals. To investigate the signific ance of ErbB2 signaling in epithelial tissues during and post development, we developed a K14-rtTA/TetRE-ErbB2 'Tet-On' bitransgenic mouse system. The se mice were normal until the ErbB2 transgene mas induced by exposure to do xycycline (Dox). Prenatal induction resulted in perinatal death. Postnatall y, ErbB2 transgene expression was observed at 4 h after the initiation of D ox, and reached a plateau at 24 h. Skin hyperplasia followed after 2 days a nd these changes reverted to normal upon Dox withdrawal. In adults, as in t he neonates, prolonged ErbB2 induction caused prominent skin and hair folli cle hyperplasias. Severe hyperplasias in the cornea, eye lids, tongue and e sophagus mere also observed. ErbB2 transgene induction was accompanied by i ncreased expression of TGF alpha, a ligand of epidermal growth factor recep tor (EGFR), and to a lesser extent, EGFR, further enhancing RTK signal tran sduction. We conclude that ErbB2 plays important roles in both development and maintenance of hair follicles and diverse squamous epithelia and that t his ligand-inducible and tissue-specific 'Tet-On' transgenic mouse system p rovides a means to study transgenes with perinatal toxicity.