Helen Salz, PhD
Professor, Genetics and Genome Scienceshks@case.edu 216.368.2879 (o) 216.368.3432 (f)
Member, Molecular Oncology Program
In the healthy adult, tissue maintenance and repair depends on a stable population of stem cells that have the capacity to give rise to both self-renewing and differentiating daughter cells. Studies in the Drosophila ovary, a powerful system for the study of adult stem cells, illustrate that the decision to exit the stem cell state and enter the appropriate differentiation pathway requires the coordinate regulation of specific signaling pathways, transcription factors and RNA binding proteins. New studies emerging from my laboratory have revealed that adult female germline stem cells must also remember their sex as they enter the differentiation pathway or risk tumor formation.
Post-transcriptional gene regulation: Understanding tissue- and stage-specific gene regulation remains one of the central issues in developmental biology. Studies of developmentally important genes, such as those that specify and maintain cell fate, have revealed that many genes are regulated post-transcriptionally. Our work has established that sex determination in the fruit fly Drosophila melanogaster is a powerful tool for understanding tissue-specific post-transcriptional gene regulation in the living animal. Much of our work has focused on Sex-lethal (Sxl), the RNA binding protein encoding binary switch gene that regulates all aspects of female-specific development and behavior. Using experimental strategies that combine the strength of Drosophila genetics, cell biology and biochemistry, we elucidated how Sxl, once activated, controls its own expression by a positive feedback splicing mechanism. Current work in the laboratory is focused on understanding how Sxl controls expression of the downstream gene regulatory networks responsible for sexually dimorphic cellular fates and behaviors.
Adult stem cells and tumors: Information about adult stem cell behavior is not only necessary to understand how healthy cells replace damaged cells in adult tissues, but also for understanding the origins of cancer. In the healthy adult, tissue maintenance and repair depends on a stable population of stem cells that have the capacity to give rise to both self-renewing and differentiating daughter cells. Control of the self-renewal/differentiation process depends on cell autonomous determinants and on extrinsic cell-cell interactions with the cellular microenvironment. Regulated execution of the self-renewal/differentiation choice is critical because an excess of differentiation can lead to stem cell depletion and tissue senescence, whereas a failure to enter the differentiation pathway can lead to an accumulation of proliferating cells and tumor formation.
New studies emerging from our laboratory demonstrate a previously unknown role for Sxl in controlling the self-renewal/differentiation decision of germline stem cells in the adult ovary. We have observed that blocking stem cell differentiation leads to an ovary filled with tumorous germ cells. Current work in the laboratory is focused on providing information about the post-transcriptional regulatory strategy used by adult stem cells to make the self-renewal/differentiation switch during normal development and at developing an understanding of why the failure to make this switch triggers malignant transformation.
Translational Impact: The Drosophila ovary is a powerful genetic system for studying how stem cells behave in their natural environment because the stem cells can be easily located, genetically manipulated, and observed without destroying tissue architecture. Given the deep conservation of stem cell behavior and regulatory mechanisms across species, we are confidant that the information obtained from studies in the fly will reveal concepts important for understanding the mechanism underlying cancer and may, in the future, lead to the design of effective strategies to restrict tumor growth or even correct the errors that lead to cancer.