EXPRESSION OF A DOMINANT-NEGATIVE TYPE-II TRANSFORMING GROWTH-FACTOR-BETA (TGF-BETA) RECEPTOR IN THE EPIDERMIS OF TRANSGENIC MICE BLOCKS TGF-BETA-MEDIATED GROWTH-INHIBITION

To determine whether a functional type II receptor of transforming gro wth factor beta (TGF-beta) is required to mediate the growth inhibitor y effect of TGF-beta on the skin in vivo, we have generated transgenic mice that overexpress a dominant negative-type II TGF-beta receptor ( Delta beta RII) in the epidermis, The Delta beta RII mice exhibited a thickened and wrinkled skin, and histologically the epidermis was mark edly hyperplastic and hyperkeratotic. III vivo labeling with BrdUrd sh owed a 2.5-fold increase in the labeling index over controls, with lab eled nuclei occurring in both basal and suprabasal cells of transgenic epidermis, In heterozygotes, this skin phenotype gradually diminished , and by 10-14 days after birth the transgenic mice were indistinguish able from their normal siblings. However, when F-1 mice were mated to homozygosity, perinatal lethality occurred due to the severe hyperkera totic phenotype, which restricted movement, Cultured primary keratinoc ytes from Delta beta RII mice also exhibited an increased rate of grow th in comparison with nontransgenic controls, and were resistant to TG F-beta-induced growth inhibition, These data document the role of the type II TGF-beta receptor in mediating TGF-beta-induced growth inhibit ion of the epidermis in vivo and in maintenance of epidermal homeostas is.