Margaret T. Fuller
Board Member: 2002 - 2005
Regulation of Stem Cell Behavior
Cell Type Specific Transcription Machinery and Tissue Specific Gene Expression
Cell Cycle and Cell Morphogenesis During Male Gametogenesis
Mechanism of Cytokinesis
A major focus of our work concerns the mechanisms that regulate stem cell behavior. Many highly differentiated but short-lived cell-types, including blood, skin, and sperm, are produced throughout adult life from stem cells. The central characteristic of stem cells is their remarkable, long-term capacity to divide as relatively undifferentiated precursors while also producing daughter cells that initiate differentiation. Understanding the mechanisms that regulate stem cell specification and the choice between stem cell self-renewal and differentiation is crucial for realizing the potential of stem cells for regenerative medicine. We are using the Drosophila male germ line as a powerful genetic system to identify both the cell autonomous determinants and the extrinsic cell-cell interactions that govern stem cell behavior. Our results indicate that signals from surrounding somatic support cells specify asymmetric division of male germ line stem cells by inducing one daughter cell to self-renew stem cell identity while directing the other daughter cell to differentiate.
A second focus of our work concerns a central question in both developmental and cell biology: How does the developmental program remodel fundamental cellular functions like the cell cycle, the cytoskeleton, and the general transcription machinery to give rise to specialized cell types during cellular differentiation? We investigate the mechanisms that regulate and mediate cellular differentiation during male gametogenesis, using spermatogenesis in Drosophila a powerful genetic model system. Our current work focuses on three areas. 1) We are investigating the mechanisms that regulate the unique program of gene expression that takes place in primary spermatocytes in preparation for the dramatic morphogenetic events of spermatid differentiation. We have discovered that both progression of the meiotic cell cycle and expression of spermatid differentiation genes are regulated by tissue specific versions of the general PolII transcription machinery. In addition, our work implicates components upstream of the Rb pathway in the control of terminal differentiation. 2) We are exploring the mechanisms that regulate remodeling of sub-cellular organelles. Our studies revealed the first known protein mediator of mitochondrial fusion, required for formation of specialized mitochondrial structures in spermatids. Our current work indicates that human homologs of the Drosophila mitofusin protein regulate mitochondrial morphology in human cells and may play a role in apotosis as well. 3) We are dissecting the mechanisms that remodel the actin cytoskeleton and lead to localized assembly and constriction of the acto-myosin contractile machinery during cytokinesis. We have identified mutations in over 20 new genes that block different stages of contractile ring assembly and function during male meiosis. To investigate the underlying molecular mechanisms that regulate and mediate cytokinesis, we are cloning selected of these genes. Our initial results indicate that shared mechanisms involving addition of new membrane are required for both cleavage furrow constriction during cytokinesis and polarized cell elongation during later terminal differentiation.