The TGF-beta family of polypeptides consists of multifunctional peptides involved in growth and differentiation. TGF-beta1 and 2 have been detected in the skin during embryonic development. Embryonic upper lip skin grown in organ culture can be manipulated to study the effects of specific agents on skin development. The objective of this study is to use an organ culture model to study the role and mechanisms of TGF-beta action in skin development and disease. We intend to i) determine which growth factors promote skin development in embryonic organ culture, ii) characterize the effects of exogenous TGF-beta1 on skin development, and iii) use organ cultures from genetically altered mice to determine the role of tumor suppressor proteins, p52, pRb, and p107, on skin development and responsiveness to TGF-beta1. Differentiation of keratinocytes will be monitored by immunohistochemical staining of specific keratins. The effects of TGF-beta on bromodeoxyuridine incorporation and Myc gene regulation will be investigated. TGF-beta signals through a heteromeric receptor complex consisting of type I and type II serine/threonine kinases. We have generated transgenic mice which express a dominant-negative TGF-beta type II receptor under the control of a metallothionien promoter (MTDNIIR). The dominant-negative receptor has been shown to block responsiveness to TGF-beta in cells in culture and the metallothionien promoter allows the transgene to be regulated with zinc. To determine the role of endogenous TGF-beta in skin development, skin cultures from wild type and MTDNIIR embryos grown in the presence and absence of zinc will be compared. Investigation of the role of TGF-beta in skin development would have significance in understanding physiological and pathological processes in the skin including wound healing and carcinogenesis.
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