Expression of a Dominant-Negative Type II Transforming Growth Factor β (TGF-β ) Receptor in the Epidermis of Transgenic Mice Blocks TGF-β -Mediated Growth Inhibition

• Published in: Proceedings of the National Academy of Sciences - PNAS 1997-03, Vol.94 (6), p.2386-2391
• Main Authors: Wang, Xiao-Jing, Greenhalgh, David A., Bickenbach, Jackie R., Jiang, Aibo, Bundman, Donnie S., Krieg, Thomas, Derynck, Rik, Roop, Dennis R.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Animals, Newborn; Biological Sciences; Cell Division - drug effects; Cell growth; Cells, Cultured; Epidermis; Epidermis - drug effects; Epidermis - pathology; Epidermis - physiology; Epitopes - chemistry; Female; Genes, myc; Humans; Hypertrophy; Keratinocytes; Keratinocytes - cytology; Keratinocytes - drug effects; Keratinocytes - physiology; Keratosis - genetics; Male; Mice; Mice, Inbred ICR; Mice, Inbred Strains; Mice, Transgenic; Mitotic Index; Phenotypes; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-myc - biosynthesis; Receptor, Transforming Growth Factor-beta Type II; Receptors; Receptors, Transforming Growth Factor beta - biosynthesis; Skin; Skin - pathology; Skin Aging; Skin Physiological Phenomena; Transforming Growth Factor beta - pharmacology; Transgenes; Transgenic animals; Transgenic plants
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.94.6.2386

To determine whether a functional type II receptor of transforming growth factor β (TGF-β ) is required to mediate the growth inhibitory effect of TGF-β on the skin in vivo, we have generated transgenic mice that overexpress a dominant negative-type II TGF-β receptor (Δ β RII) in the epidermis. The Δ β RII mice exhibited a thickened and wrinkled skin, and histologically the epidermis was markedly hyperplastic and hyperkeratotic. In vivo labeling with BrdUrd showed a 2.5-fold increase in the labeling index over controls, with labeled 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 indistinguishable from their normal siblings. However, when F1mice were mated to homozygosity, perinatal lethality occurred due to the severe hyperkeratotic phenotype, which restricted movement. Cultured primary keratinocytes from Δ β RII mice also exhibited an increased rate of growth in comparison with nontransgenic controls, and were resistant to TGF-β -induced growth inhibition. These data document the role of the type II TGF-β receptor in mediating TGF-β -induced growth inhibition of the epidermis in vivo and in maintenance of epidermal homeostasis.