This laboratory investigates genetic pathways that control developmental programs in mammary epithelium, germ cells and hematopoietic cells. Common to these cell types is their need for cytokines to induce cell proliferation, survival and differentiation. We investigated the role of genes through their deletion from the mouse genome, which should provide insight into their true in vivo function. Two main experimental approaches are being employed, the deletion of genes from the mouse germline and the inactivation of genes in specific cell types within the mouse using the Cre-loxP recombination system. Research published in the current reporting period focused on several signaling cascades, including the Jak2-Stat5 pathway, Stat3, PPARg, the arylhydrocarbone receptor and its nuclear translocator, sonic hedgehog and Bcl-x. We demonstrated that Jak2 and Stat5 are required for the specification, proliferation and differentiation of mammary epithelium. In contrast Stat3 is required for the death and remodeling of mammary tissue during involution. The bcl-x gene, which encodes a cell-survival protein, had been proposed to be a direct target gene of the transcription factor Stat5 and possibly Stat3. We could demonstrate Stat5 is not the activator of the bcl-x gene in vivo. However, it is clear from our studies that the loss of Bcl-x interferes with the controlled remodeling of mammary tissue. Loss of Bcl-x leads to a reduced apoptosis during involution and the maintenance of functional tissue. Furthermore, we demonstrated that Bcl-x is required for the maintenance of the corpus luteum and follicles in the postnatal ovary. Based on tissue culture studies, PPARg was believed to be important for mammary tumorigenesis and possibly normal development. Since loss of the PPARg gene leads to embryonic lethality we deleted the gene specifically in mammary epithelium and in a second study in follicles and the corpus luteum. Mammary tissue developed normally its absence and a first study did not demonstrate accelerated tumor development with the first year of life. Similarly, the loss of the arylhydrocarbone receptor and its nuclear translocator ARNT did not alter normal mammary development nor did it induce neoplasias. Nevertheless, we determined that both, the PPARg and ARNT are necessary for normal follicular development and fertility. In search of genes that control the specification of mammary epithelium we extended our studies on the b-catenin signaling pathway. b-catenin is involved in specification processes in the skin and the mammary gland is an evolutionary derivative of the epidermis. Indeed we could demonstrate that the activation of b-catenin signaling in differentiated mammary epithelium leads to the transdifferentiation into epidermal-like structures. From this we concluded that the relative quiescence of b-catenin signaling is required for the maintenance of differentiated mammary epithelium. Lastly, we demonstrated that activation of different parts of the wnt signaling pathway in mammary epithelium leads to the stabilization / activation of b-catenin and thus the transdifferentiation into epidermal like structures. Thus, wnt signaling in mammary tissue does not only induce tumors but also participates in the specification of cells.
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