The long-term objective of the proposed work is to understand the roles of the Transforming Growth Factors-beta1, -beta2, and -beta3 in mammalian development. TGFbetas are closely related members of a large family of structurally similar polypeptides with pronounced embryonic expression in areas undergoing tissue morphogenesis. Specifically, the aims of this research are to characterize the multiple developmental abnormalities caused by the mutant genes. This is now possible because for the first time one has animals and derivative organs, tissues, and cells with specific mutations in each of these genes. Genetic, surgical, and biochemical means will be used to suppress developmental events which lead either to a lethality, or which themselves suppress the presentation of defects. In this way other developmental abnormalities can be characterized. For example, the cleft palate of the TGFbeta3 homozygous mutant animals will be repaired by surgical or biochemical means to allow the mutant animals to develop to maturity. In this way the possible roles of TGFbeta3 in the regulation of mammary gland development and in wound healing could be investigated. Also, the maternal transfer of TGFbeta1 to homozygous mutant embryos which may rescue them from developmental abnormalities will be eliminated by genetic manipulations designed to increase the longevity of homozygous mutant mothers. In this way the embryos can develop in the absence of both embryonic and maternal TGFbeta1, thereby exposing other developmental defects. The morphogenetic processes involving epithelial-mesenchymal transformations in both secondary palate fusion and atrioventricular valve and septum formation will be investigated in organ culture systems where molecular and biochemical manipulations are possible. The significance of these studies for understanding aspects of human development and the mechanisms underlying serious congenital malformations, and for improving our ability to treat human disease is high. The TGFbeta3 knockout mouse will provide us with the tool to understand the molecular players involved in the development of cleft palate, which is one of the most prevalent disfiguring congenital malformations in humans. In heart development, the TGFbeta knockout mice may allow us to definitively determine which TGFbetas are playing specific roles in the development of heart valves and septa, tissues which are affected in the majority of congenital heart defects. Finally, since TGFbeta2 may play critical roles in implantation and immune suppression of the maternal immune surveillance system during pregnancy, the TGFbeta2 knockout mouse may have potential for testing reproductive therapies.
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