Adult stem cells can renew themselves at each division and generate terminally differentiated progeny that maintain homeostasis in adult tissues. A major issue in understanding adult stem cells has been to distinguish whether regulation is primarily controlled by internal or external mechanisms. In mammalian systems, stromal cells have been hypothesized to form special microenvironments or niches for stem cells. Due to the difficulty in identifying stem cells and surrounding stem cells in vivo, there is little known about the structure and function of stem cell niches. Recently, we have demonstrated the existence of germline stem cell (GSC) niches in the Drosophila ovary, where stem cells and their surrounding cells can be effectively studied in vivo. We have also identified decapentaplegic (dpp), encoding a TGF-beta-like growth factor, as a key signal from the niche cells regulating GSC self-renewal and division. However, there are still many questions that remain to be answered regarding how the niche regulates GSCs. The long-term goal of this project will be to gain a greater understanding of how the niches regulate stem cells, and of dpp and other signaling pathways involved in the communication between stem cells and their niches, and of intrinsic factors in stem cells that interpret these signals. We will focus on how the dpp pathway regulates GSC self-renewal and differentiation. Our genetic screens have identified mutants that affect GSC self-renewal and differentiation. Further molecular characterization of some of these mutants will reveal important molecular mechanisms regulating GSCs. The mechanisms controlling GSCs in the Drosophila ovary are likely to be fundamental to the understanding of adult mammalian stem cells since stem cells from diverse organisms share similar """"""""stem"""""""" properties. In addition, a better understanding of the mechanisms regulating stem cells is of considerable clinical relevance, since the pathways and genes involved will provide valuable information for using stem cells clinically and for treating some degenerative diseases and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM064428-01
Application #
6416428
Study Section
Genetics Study Section (GEN)
Program Officer
Greenberg, Judith H
Project Start
2002-01-01
Project End
2006-12-31
Budget Start
2002-01-01
Budget End
2002-12-31
Support Year
1
Fiscal Year
2002
Total Cost
$248,011
Indirect Cost
Name
Stowers Institute for Medical Research
Department
Type
DUNS #
City
Kansas City
State
MO
Country
United States
Zip Code
64110
Pan, Lei; Wang, Su; Lu, Tinglin et al. (2014) Protein competition switches the function of COP9 from self-renewal to differentiation. Nature 514:233-6
Ma, Xing; Wang, Su; Do, Trieu et al. (2014) Piwi is required in multiple cell types to control germline stem cell lineage development in the Drosophila ovary. PLoS One 9:e90267
Tian, Jianjun Paul; Jin, Zhigang; Xie, Ting (2012) Mathematical model for two germline stem cells competing for niche occupancy. Bull Math Biol 74:1207-25
Kirilly, Daniel; Wang, Su; Xie, Ting (2011) Self-maintained escort cells form a germline stem cell differentiation niche. Development 138:5087-97
Chen, Shuyi; Wang, Su; Xie, Ting (2011) Restricting self-renewal signals within the stem cell niche: multiple levels of control. Curr Opin Genet Dev 21:684-9
Wang, Xiaoxi; Pan, Lei; Wang, Su et al. (2011) Histone H3K9 trimethylase Eggless controls germline stem cell maintenance and differentiation. PLoS Genet 7:e1002426
Chen, Shuyi; Kaneko, Satoshi; Ma, Xing et al. (2010) Lissencephaly-1 controls germline stem cell self-renewal through modulating bone morphogenetic protein signaling and niche adhesion. Proc Natl Acad Sci U S A 107:19939-44
Shen, Run; Weng, Changjiang; Yu, Junjing et al. (2009) eIF4A controls germline stem cell self-renewal by directly inhibiting BAM function in the Drosophila ovary. Proc Natl Acad Sci U S A 106:11623-8
Xie, T; Song, X; Jin, Z et al. (2008) Interactions between stem cells and their niche in the Drosophila ovary. Cold Spring Harb Symp Quant Biol 73:39-47
Jin, Zhigang; Kirilly, Daniel; Weng, Changjiang et al. (2008) Differentiation-defective stem cells outcompete normal stem cells for niche occupancy in the Drosophila ovary. Cell Stem Cell 2:39-49

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