Conditional epidermal expression of TGF beta 1 blocks neonatal lethality but causes a reversible hyperplasia and alopecia

To study the role of transforming growth factor type beta1 (TGF beta1) in e pidermal growth control and disease, we have generated a conditional expres sion system by using the bovine keratin 5 promoter to drive expression of t he tetracycline-regulated transactivators tTA and rTA, and a constitutively active mutant of TGF beta1 linked to the tetO target sequence for the tran sactivator. This model allows for induction or suppression of exogenous TGF beta1 with oral doxycycline. Maximal expression of TGF beta1 during gestat ion caused embryonic lethality, whereas partial suppression allowed full-te rm development with neonatal lethality characterized by runting, epidermal hypoproliferation, and blocked hair follicle growth. With complete suppress ion, phenotypically normal double transgenic (DT) mice were born. Acute ind uction of TGF beta1 in the epidermis of adult mice inhibited basal and foll icular keratinocyte proliferation and reentry of telogen hair follicles int o anagen. However, chronic expression of TGF beta1 in adult DTs caused seve re alopecia characterized by epidermal and follicular hyperproliferation, a poptosis, as well as dermal fibrosis and inflammation. Readministration of doxycycline to tTA DT mice caused hair regrowth within 14 days. The mRNA an d protein for Smad7, an inhibitor of TGF beta signaling, were up-regulated in the epidermis and hair follicles of alopecic skin and rapidly induced in rTA mice in parallel with the TGF/31 transgene, suggesting that the hyperp roliferative phenotype may result in part from development of a sustained n egative feedback loop. Thus, this conditional expression system provides an important model for understanding the role of TGF beta1 during development , in normal skin biology, and in disease.