Margaret
T. Fuller, Ph.D
Stem cells play a critical role the regeneration of many differentiated but short-lived cell types such as blood, skin, and sperm throughout adult life. We are using the Drosophila male germ line as a model system to investigate the mechanisms that regulate stem division and the crucial choice between self-renewal and differentiation that maintains stem cell populations in vivo. Drosophila male germ line stem cells can be identified and visualized in vivo, in the context of their normal anatomy, allowing investigation of the role of surrounding support cells in regulating stem cell behavior. We have demonstrated that a support cell niche regulates stem cell self-renewal via activation of the JAK-STAT signaling pathway in adjacent male germ line stem cells. In addition, we found that a second set of nearby somatic cyst cells play a guardian role, ensuring that the germ cell displaced outside of the niche differentiate.
Our work has established the Drosophila male germ line as a powerful system for investigating the mechanisms that regulate stem cell self-renewal and differentiation. We now aim to exploit this system and the tools we have developed to identify and test the function of intrinsic determinants that act in stem cells to specify stem cell self-renewal in response to the signals from the niche. We will use both genomics and traditional Drosophila genetics to identify additional genes that regulate stem cell behavior, either intrinsically or through action in surrounding support cells. We will also test whether the niche mechanism and signaling pathways we have discovered govern self-renewal and differentiation of other stem cell populations in Drosophila and in mammals.
Cell differentiation requires mechanisms to modify many fundamental cellular processes like the cell cycle, the cytoskeleton, organelle structure and even the transcription machinery under control of the developmental program. We are using male gametogensis as a model system to investigate the underlying mechanisms that specify cellular differentiation. Using this system we identified the first known protein mediator of mitochondrial fusion. We are currently investigating the mechanisms that mediate cytokinesis and polarized cell outgrowth. We have uncovered mechanisms that regulate progression of the specialized cell cycle of meiosis. Finally, we have discovered that tissue specific forms of the general transcription machinery selectively regulate cell type specific gene expression programs during development.