Molecular Genetic Study of Stem Cell and Cancer Stem Cell Regulation in Drosophila and Mice I identified mutations in the Drosophila stat gene and developed a fly model for studying the JAK/STAT signal transduction pathway (Hou et al., Cell, 1996) during my postdoctoral research at Harvard Medical School. After I moved to NCI, my group identified a receptor for the JAK/STAT signal transduction pathway (Chen et al., Genes Dev., 2002);we also found that the JAK/STAT pathway and Cyclin D/Cdk4 cooperatively regulate tumor development in fly blood and eye (Chen et al., Dev. Cell, 2003). Over the course of our work, we accumulated a number of reagents for studying the JAK/STAT signaling in Drosophila. Using these tools, we demonstrated that a RapGEF/Rap signal regulates stem cell anchoring to the niche through its interactions with the JAK/STAT signal transduction pathway (Wang et al., Dev. Cell, 2006). We also identified adult kidney multipotent renal and nephric stem cells (RNSCs) in Drosophila Malpighian tubules (MTs) and demonstrated that an autocrine JAK/STAT signal regulates kidney stem cell self-renewal (Singh et al., Cell Stem Cell, 2007). This was the first in vivo evidence that the adult animal kidney is maintained by multipotent stem cells. Our paper was selected by 1000 faculties in 2007 and I was invited by the editor (Dr. Eric G. Neilson) of the Journal of the American Society of Nephrology to write a review on kidney stem cells. We also performed a genetic screen for mutations in the MTs and have so far identified mutations in 20 genes that affect RNSC fates. Among them, we found that mutations in the oncogene Ras and several Drosophila tumor suppressor genes (such as scrib, sav, and lats) cause RNSC overproliferation without differentiation and cause the migration of normally quiescent stem cells. We have termed these cells, migratory cancer stem cells. As an opposite phenotype, we found that mutations in Drosophila homologues of the tumor suppressor LKB1 and kidney tumor suppressor BHD cause the RNCS to differentiate early. We have several projects in progress. The first project is to investigate how the two groups of oncogene and tumor suppressor genes regulate the adult kidney stem cell fates in the Drosophila model system. Our second project is to extend our findings from the Drosophila MTs to the mouse kidney. We obtained a conditional knockout for mouse scrib1 (the mouse homologue of the fly tumor suppressor gene scrib) from Dr. Neal Copeland and Nancy Jenkins and are in the process of generating a conditional knockout for sav1 (the mouse homologue of the fly tumor suppressor gene sav). We will study the functions of scrib1 and sav1 in mouse kidney stem cells and cancer stem cells. We are also developing a mosaic expression and analysis with double markers (MEADM) technique for lineage tracing and to study the regulation of mouse kidney stem cells by the mouse homologues of the above fly genes. Our third project is to study RapGEf2s functions in HSC-niche interaction, angiogenesis, and tumor-microenvironment interactions in mice. This is possible, because we have identified the mouse homologue (RapGEF2) of the fly RapGEF and generated RapGEF2 conditional knockout mice. The RapGEF2-deficient mice have vascular and hematopoietic stem cell (HSC) defects. By taking 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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