1. How does the JAK/STAT pathway regulate stem cells numbers? Regulating the number of stem cells is a primary mechanism by which homeostasis is maintained and oncogenesis is prevented. Stem cells divide to produce daughter cells that renew the stem cell pool or that regenerate tissue by differentiating. The choice between self-renewal and differentiation must be tightly controlled as increasing the stem cell pool provides a condition for oncogenesis. Tumors have cancer stem cells that self-renew and establish new tumors at low numbers. One of the critical regulators of stem cell numbers in mammals is the JAK/STAT pathway. Furthermore, dominant-active mutations in jak and stat genes cause cancer, and Stat3 is a target for therapeutic intervention since its ablation blocks the growth of human cancer cells. Despite these compelling observations, the mechanisms utilized by this pathway to regulate stem cell numbers in mammals have not yet been elucidated, in part due to the redundancy of 4 jak and 7 stat genes. Drosophila provides an ideal system to study how JAK/STAT signaling regulates stem cell numbers, as this function is conserved in several Drosophila tissues, including testis and eye. Unlike the redundancy of the mammalian system, Drosophila has only one jak and one stat gene (called stat92E), which allows facile in vivo analysis. Despite these advantages, nothing is known mechanistically about how this pathway controls stem cell populations in Drosophila. Previous work has shown that over-expression of the cytokine Unpaired, which activates JAK/STAT signaling, leads to an expansion of stem/progenitor cells in the eye and testis. We find that these overgrowths depend on activation of Stat92E within stem cells. Our current hypothesis is that Stat92E must regulate three distinct processes in stem cells in order to regulate their numbers: it must increase cellular mass and accelerate cell cycle progression and, after mitosis, promote self-renewal in some daughter cells. Since Stat92E is a transcription factor, discrete Stat92E target genes should mediate its effects on these processes. We have identified several genes with human homologs that may lie directly downstream of Stat92E and may regulate self-renewal, cellular growth and cell cycle in stem cells.
Associate Professor, Department of Biochemistry and Molecular Pharmacology
PhD from Washington University at Saint Louis
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