Cell Fate Decisions in Epithelial Stem Cell Lineages

University Of California, San Francisco, San Francisco CA

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Abstract

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. My lab is interested in understanding how cellular differentiation is controlled within a continuously renewing epithelial tissue. Conserved features of these tissues that are not fully understood include a flexible niche structure, a “transit amplification” stage which typically has significant cellular plasticity, and the ability of neighboring stem cell lineages to compete for niche occupancy. To understand these emergent properties of tissues, we have focused on approaches that allow for the study of cell behaviors within the native, in vivo context at cellular resolution. Our primary model system is the follicle epithelium of the Drosophila ovary, and we have recently extended our studies to Drosophila germ cells, mouse intestinal stem cells, and human embryonic stem cells. Our highly collaborative work over the past five years has resulted in 11 publications and preprints. These include the creation of a single-cell atlas of the fly ovary, the discovery of a role for JNK signaling in follicle cell differentiation, the identification of a new sensor of nutritional cues in germ cells, and the development of a high-throughput fecundity assay. We have also extended our work into mammalian stem cells with our studies of DLG1 and the intracellular pH gradient in the mouse intestinal epithelium, and our finding that actin dynamics regulate dedifferentiation of human embryonic stem cells. Our current studies are investigating three interconnected areas. First, we are studying the genetic networks that regulate cell fate. In unpublished studies, we discovered that four of the signaling pathways that govern follicle cell differentiation operate in two functionally distinct axes and that this separation of function may provide a failsafe mechanism that guards against the formation of lethal tumors. We have also made progress on understanding the mechanisms of stem cell niche competition. These projects provide us with multiple orthogonal strategies for understanding the genetic networks that regulate cell fate. Second, we are studying the cell biology of cell fate specification. Our preliminary data provide strong rationale for investigating how two transcription factors, klumpfuss and FoxK, regulate cell fate in response to changes in the intracellular pH of follicle cells and for understanding the role of somatic ring canals in follicle cell fate specification. Third, we are investigating how age-related phenotypes in ovarian somatic cells contribute to the decline in fecundity with age. Based on our preliminary data, our initial focus will be on the role of declining hormone signaling.