The Laboratory of Genetics and Physiology explores genetic programs that control the establishment and functional differentiation of diverse cell types, including mammary epithelium, hematopoietic lineages, the prostate and skin. A common denominator to these cell types is their need for cytokines to control cell proliferation, survival and differentiation and death. In particular, this laboratory investigates wnt/beta-catenin signaling and the Jak/Stat pathway, which is activated by a diverse set of cytokines, including interleukins, growth hormone and prolactin. Emphasis is on how these pathways intersect with other developmental cues, such as steroid receptors and modulating transcription factors. Moreover, authentic biological functions of these cytokine pathways are discovered through the use of experimental mouse genetics and an emphasis has been on the development of the mammary gland. Past work from this laboratory has established that the transcription factor Stat5 controls proliferation and differentiation of mammary epithelium during pregnancy, while Stat3 controls cell death during involution. Research published in the current reporting period has established that interleukin 6 is an inducer of Stat3-mediated cell death. Future work will be directed towards other cytokines that control cell death in mammary tissue and the receptors involved. Moreover, it was established that activation of the wnt/beta-catenin pathway in differentiated mammary and prostate epithelia results in the loss of cell identity and the establishment of squamous metaplasias. Using cDNA microarrays genes have been identified that are linked to the transdifferentiation process. These experiments have established that epithelial cells programmed to undergo functional differentiation retain a """"""""memory"""""""" and are able to escape through a default pathway. The default pathway reflects the ancestry of the respective cell type, which in this case is reminiscent of skin and its appendages. In a quest to further understand the non-hormonal cues that control the development and differentiation of mammary epithelium we identified the helix-loop-helix protein Id2 as an essential component for the proliferation of the emerging epithelial cell. However, Id2 is not required for mammary epithelial cells to undergo specification and acquire an activatable prolactin-Jak2-Stat5 pathway. Differentiation of mammary epithelium progresses through distinct stages and characteristic indicator proteins were identified. Using these markers a protocol of proteotyping was established, which allowed the molecular characterization of mouse mutants that exhibits lesions in mammary development. It is now possible to stage these mutants and determine at what stage epithelial development ceased. LGP has established biochemical and genetic resources (gene knock-out mice and mice expressing Cre recombinase in different cell types), which facilitated collaborations on the roles of other signaling pathways in normal mammary development and neoplastic transformation. Among them were studies on the role of the cytokine recptor erbB4, the selenocysteine tRNA, Smad3, the insulin-like growth factor I, the establishment of mammary imaging techniques, and lastly the role of the tumor suppressor gene 101 (TSG101) in mammary tumorigenesis. This project was initiated seven years ago by a former post-doc in my laboratory and now culminated in the inactivation of the TSG101 specifically in mammary epithelium of mice. A role of TSG101 in the functional differentiation of mammary epithelium was established. However, and in contrast to extensive in vitro studies by others, TSG101 did not behave like a tumor suppressor in vivo. Similarly, based on in vitro studies PPAR gamma had been suggested to be a tumor suppressor, a function we could not verify using experimental mouse genetics.
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