Regulation of Stem Cell Self-renewal and Differentiation NIH 1 R01 GM080501 Adult stem cells are required throughout life to replenish differentiated cells and repair damaged tissue. The molecular mechanisms that maintain and keep in check adult stem cell populations are key for harnessing the potential of adult stem cells for regenerative medicine as well as understanding the genesis and biology of cancer. We propose to investigate how interactions with the local environment of the stem cell niche maintain populations of germ line stem cells in the Drosophila testis, a powerful system for study of adult stem cells in vivo in the context of their niche. In previous funding cycles, we discovered that somatic support cells in the testis stem cell niche provide a crucial microenvironment that regulates both stem cell self renewal and differentiation, and that germ line stem cells (GSCs) orient toward this niche to set up a stereotyped mitotic spindle, ensuring the normally asymmetric outcome of GSC divisions. We showed that a cytokine like signal from the somatic hub activates the transcription factor STAT in GSCs and their partner somatic cyst stem cells (CySCs) and that activated STAT is critical for maintenance of CySC identity and GSC attachment to the hub. CySCs are an important component of the GSC niche and can maintain GSCs in ectopic sites away from the hub. We also found that germ cells require a """"""""go differentiate"""""""" signal from somatic cyst cells to exit limitless stem cell proliferation and enter the spermatogonial program of limited transit amplifying (TA) divisions then differentiation. These findings highlight a new model for how signals from the niche regulate stem cell self- renewal, in which timely transition from stem to TA cell is choreographed by a balance between counteracting self-renewal and differentiation signals. We now propose to utilize the powerful system and tools we have established to identify the molecular circuitry that regulates stem cell behavior in response to cues from the niche. We will investigate how GSCs attach to and orient toward the hub and how this normal behavior is controlled by the Upd signal from the hub through activation of the transcription factor STAT. We will investigate whether CySCs maintain GSCs by sending a """"""""self renew"""""""" signal or blocking a """"""""go differentiate"""""""" signal and test candidate signaling mechanisms and regulators to understand how the niche regulates stem cell fate and how the actions of two stem cell types within the same niche are coordinated. Finally, we will test the model that activation of the EGFR in somatic cyst cells by a signal from cystoblasts downregulates the CySC program, allowing a timely switch from stem cell to progenitor state in both the germ line and somatic lineages.

Public Health Relevance

The results of the proposed studies will establish paradigms for how the tissue microenvironment regulates self-renewal and differentiation of adult stem cells, which are centrally important for tissue maintenance and repair for many cell types in the human body. Understanding how support cell niches regulate adult stem cell behavior may illuminate how tumor stroma support cancer stem cells and how stem cells maintained in their normal environment may be restrained from uncontrolled proliferation by signals from support cells that trigger differentiation.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
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Haynes, Susan R
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Stanford University
Anatomy/Cell Biology
Schools of Medicine
United States
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Voog, Justin; Sandall, Sharsti L; Hime, Gary R et al. (2014) Escargot restricts niche cell to stem cell conversion in the Drosophila testis. Cell Rep 7:722-34
Shields, Alicia R; Spence, Allyson C; Yamashita, Yukiko M et al. (2014) The actin-binding protein profilin is required for germline stem cell maintenance and germ cell enclosure by somatic cyst cells. Development 141:73-82
Morillo Prado, Jose Rafael; Srinivasan, Shrividhya; Fuller, Margaret T (2013) The histone variant His2Av is required for adult stem cell maintenance in the Drosophila testis. PLoS Genet 9:e1003903
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Chang, Yi-Jie; Pi, Haiwei; Hsieh, Chang-Che et al. (2013) Smurf-mediated differential proteolysis generates dynamic BMP signaling in germline stem cells during Drosophila testis development. Dev Biol 383:106-20
Srinivasan, Shrividhya; Mahowald, Anthony P; Fuller, Margaret T (2012) The receptor tyrosine phosphatase Lar regulates adhesion between Drosophila male germline stem cells and the niche. Development 139:1381-90
Insco, Megan L; Bailey, Alexis S; Kim, Jongmin et al. (2012) A self-limiting switch based on translational control regulates the transition from proliferation to differentiation in an adult stem cell lineage. Cell Stem Cell 11:689-700
Lim, Jaclyn G Y; Fuller, Margaret T (2012) Somatic cell lineage is required for differentiation and not maintenance of germline stem cells in Drosophila testes. Proc Natl Acad Sci U S A 109:18477-81
Giansanti, Maria Grazia; Fuller, Margaret T (2012) What Drosophila spermatocytes tell us about the mechanisms underlying cytokinesis. Cytoskeleton (Hoboken) 69:869-81
Insco, Megan L; Leon, Arlene; Tam, Cheuk Ho et al. (2009) Accumulation of a differentiation regulator specifies transit amplifying division number in an adult stem cell lineage. Proc Natl Acad Sci U S A 106:22311-6

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