Research Topic: 'Molecular Genetic Study of Stem Cell and Cancer Stem Cell Regulation in Drosophila and Mice' Our laboratory is interested in understanding how intercellular signals regulate development in embryo and regeneration in adult. We have been studying the JAK-Stat signaling in Drosophila. From our work and that of many others, it has emerged that the same signaling controls numerous decisions in development and also regulates stem cells in various adult tissues, including testis, kidney, stomach, and intestine. Current work is directed at understanding how adult stem cells are regulated in Drosophila and mouse in vivo genetic systems. Our current projects have evolved from our earlier studies of the JAK-Stat signal transduction pathway in Drosophila. In 1996, I identified mutations in the Drosophila stat gene (working with Dr. Norbert Perrimon in Harvard Medical School) and opened the field to the use of fly genetics to understand the JAK-Stat signaling mechanisms and functions (Hou et al., Cell, 1996). Over the years, my lab in NCI has made several major discoveries in understanding of the JAK-Stat signaling, including the identification of a receptor for the JAK/STAT signal transduction pathway (Chen et al., Genes Dev., 2002) and the discovery that the JAK/STAT pathway and Cyclin D/Cdk4 cooperatively regulate tumor development in fly blood and eye (Chen et al., Dev. Cell, 2003). During a genetic screen for genes that interact with the JAK-Stat signaling in male germline stem cells (GSCs), we discovered that a RapGEF/Rap signaling regulates stem cell anchoring to the niche by regulating E-cadherin-mediated cell adhesion (Wang et al., Dev. Cell, 2006). We also generated mice carrying a conditional knockout of the RapGEF gene and found that a RapGEF/SCL pathway regulates development of haematopoietic stem cells (Satya et al., Blood, 2010). Using a GFP reporter (Stat-GFP) for the JAK-Stat signaling in Drosophila, we found that the signaling is activated in stem cells in several adult tissues and the Stat-GFP reporter can be used as a stem cell marker. Using the stem cell marker we identified adult kidney multipotent renal and nephric stem cells (RNSCs) in the Drosophila Malpighian tubules (MTs) and demonstrated that an autocrine JAK/STAT signal regulates the kidney stem cell self-renewal (Singh et al., Cell Stem Cell, 2007). The adult fly kidney stem cells are relatively quiescent and only divide once in one week. However, they can become very active and even develop stem cell tumors upon activating the JAK-STAT signal transduction pathway or expressing the activated form of the Ras oncogene (Singh et al., Cell Stem Cell, 2007; Zeng et al., JCP, 2010). The function and anatomical location of adult kidney stem cells are evolutionarily conserved from fly to fish and maybe also to mammals (Zeng and Hou, Cell Stem Cell, 2011). We recently also identified gastric stem cells (GaSCs) in the adult Drosophila gastric and stomach Organs by using the Stat-GFP reporter (Singh et al., Cell Cycle, 2011). We further found that JAK-STAT signaling regulates GaSC proliferation, Wingless signaling regulates GaSC self-renewal, and Hedgehog signaling regulates GaSC differentiation. The differentiation pattern and genetic control of the Drosophila GaSCs are remarkably similar to what are observed in the mouse gastric stem cells. In last three years, we finished the genome-wide RNAi screens in the Drosophila intestinal and male germline stem cells and identified a number of unique genes whose knockdown affect different aspects of stem cell properties. From characterizing these genes, we found that Broad relays hormone signals to regulate stem cell differentiation in Drosophila midgut during metamorphosis (Zeng and Hou, Development, 2012) and the Osa-containing SWI/SNF chromatin-remodeling complex regulates stem cell commitment in the adult Drosophila intestine (Zeng and Hou, Development, 2013). We are currently focusing on characterizing genes identified from our screens: (1) that regulate stem cell asymmetric division in the Drosophila testis; (2) genes that function in the metabolic pathways and regulate stem cell survival or cancer stem cell's potency in both adult Drosophila digestion system and mouse model. Using this cross-species approach we expect both to obtain an enhanced understanding of stem-cell regulation and to identify new targets for the treatment of human diseases.
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