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Molecular Mechanisms Governing Adult Stem Cell Regulation in Drosophila and Mice My laboratory is interested in applying a combination of molecular, genetic, genomic, developmental, and cell biological approaches to understand how adult stem cells are regulated in vivo using Drosophila and mice as model systems. An adult stem cell is defined as a cell residing in an adult tissue that can self-renew and generate differentiated cells that replace dying or damaged cells throughout an organism’s lifetime. The mechanisms governing stem cell regulation are also of great interest to understanding aging and developing treatments for degenerative diseases and cancer. However, the molecular mechanisms governing their regulation in vivo remain largely unknown. My laboratory is currently using Drosophila ovarian germline stem cells (GSCs) and somatic stem cells (SSCs) as well as mouse testicular GSCs and eye stem cells to study the molecular mechanisms underlying adult stem cell regulation in vivo. Drosophila ovarian stem cells represent an excellent genetic system for studying stem cell self-renewal, differentiation, and division at the molecular and cellular level because they can be easily identified, and the role of a given gene in stem cell regulation can be precisely determined (Xie and Spradling, 2001; Xie et al., 2005). Two or three GSCs are located at the tip of the germarium and can be easily identified by their direct contact with cap cells and the presence of a unique germ cell-specific organelle, called a spectrosome. The GSC niche in the Drosophila ovary has been the first to be defined in any system (Xie and Spradling, 2000). We have identified two BMP-like growth factors, Dpp (BMP2/4) and Gbb (BMP5-8), that are necessary and sufficient for controlling GSC self-renewal (Xie and Spradling, 1998; Song et al., 2004). Furthermore, we have shown that BMPs function as short-range niche signals and directly suppress expression of bam, which is both necessary and sufficient for differentiation of stem cell daughters (Song et al., 2004). Similarly, the GSC niche in the Drosophila testis also utilizes the same BMP signaling pathway to control GSC self-renewal partly by repressing bam expression (Kawase et al., 2004). Our studies suggest a simple model for explaining how niche signals control stem cell self-renewal. The niche provides short-range signals that directly repress expression of differentiation-promoting genes in GSCs and thereby maintain their self-renewal and simultaneously allow the other daughters lying one cell diameter away from the niche to differentiate into cystoblasts. We have demonstrated that DE-cadherin accumulates between cap cells and GSCs and is essential for anchoring GSCs in their niche (Song et al., 2002). Recent studies on mammalian stem cells have shown that cadherin molecules also accumulate between stem cells and their niche cells, suggesting that cadherin-mediated cell adhesion represents a conserved mechanism for stem cell anchorage in the niche. Finally, we have recently shown that the GSC niche forms at the larval-pupal transition stage and uses Dpp to stimulate proliferation of newly formed GSCs (Zhu and Xie, 2003). Our recent genetic screens have identified a number of new mutants that have defects in GSC self-renewal, differentiation or proliferation. Future characterization of these mutants will surely provide new insights into molecular mechanisms governing GSC regulation. We would also like to identify additional niche signals and study how these niche signals are integrated in GSCs by identifying intrinsic factors using microarrays and genetics. Two or three SSCs in the middle of the germarium generate somatic epithelial cells covering differentiated germ cells and stalk cells connecting two adjacent egg chambers. They are anchored to posterior inner sheath cells through DE-cadherin-mediated cell adhesion, and such anchorage is essential for maintaining SSCs (Song and Xie, 2002). Furthermore, we have demonstrated that Wingless (Wnt1) produced by cap cells is essential for maintaining SSCs (Song and Xie, 2003). The studies from other laboratories have shown that Hedgehog from cap cells is also essential for controlling SSC maintenance and proliferation. These studies suggest that cap cells and inner sheath cells likely form a niche for SSCs. We have recently shown that BMP and JAK-STAT signaling is also required for controlling SSC self-renewal and proliferation. We are currently investigating how these multiple signaling pathways work together to control SSC self-renewal, proliferation and differentiation. Our recent genetic screens have also identified a number of mutants that have defects in follicle cell production, some of which may result from defective SSCs. Since Hedgehog, Wnt and BMP pathways have been shown to regulate adult stem cells in mammalian systems, our future studies on SSCs will provide more insight into how adult stem cells are regulated in general. So far, studies on Drosophila stem cells and their niches have provided and will continue to provide guiding principles for understanding adult stem cells and their niches in mammalian systems. In this exciting area of stem cell biology, mammalian systems have also made rapid progress in understanding the functions of stem cells and their niches. The knowledge gained from comparative studies in multiple systems will further enhance our ability to define the common mechanisms and strategies governing stem cell self-renewal, proliferation and differentiation. My lab is also interested in investigating how the molecular mechanisms underlying stem cell regulation are conserved from Drosophila to mice using stem cells in the mouse testis and eye. Although the stem cells in these tissues have been previously studied by in vitro cultures and/or transplantation, their locations and perspective niches have not been defined. We are currently localizing GSCs and their niche in the mouse testis as well as retinal stem cells, trabecular meshwork stem cells and their niches in the mouse eye using a combination of cell biological and genetic approaches. We are also developing new tools that allow us to test the function of a given gene in stem cells and their niches, and identifying more genes that are potentially important for stem cell regulation in the mouse testis and eye using a combination of genetic, molecular, genomic and cell biological approaches. In addition, we will test whether retinal and trabecular meshwork stem cells can be used to treat glaucoma, a degenerative eye disease that causes damage in trabecular meshwork cells and degeneration of retinal ganglion cells. Our studies will eventually lead to a better understanding of stem cell regulation in the testis and eye and eventually better treatments for human infertility, testicular cancer and degenerative eye diseases. Academic Appointment: Professor, Department of Anatomy & Cell Biology, KU Medical School Selected publications |
Xie Lab