The molecular mechanisms that regulate stem cell self renewal and differentiation are crucial for embryonic development and for long term tissue maintenance and repair. Understanding these mechanisms will be key for harnessing the potential of adult stem cells for regenerative medicine. We propose to identify molecular mechanisms that regulate adult stem cell self- renewal, maintenance and asymmetric division to maintain tissue homeostasis throughout life. Using the Drosophila male germ line as a model system, we discovered that support cells provide a crucial microenvironment that regulates both stem cell self renewal and differentiation, and that stem cells orient toward this niche to set up a stereotyped mitotic spindle, ensuring the normally asymmetric outcome of stem cell divisions. 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 elucidate the cellular mechanisms that orient stem cells to the niche to specify asymmetric division and investigate how insulin receptor signaling components affect stem behavior. To elucidate the transcriptional regulatory network that specifies stem cell fate downstream of niche signals, we will investigate the regulation and mode of action of /o/a BTB domain-Zn finger protein(s), identify and investigate the function of targets of activated STAT in stem cells, and place genes that regulate stem cell behavior in the context of known stem cell regulatory pathways. To investigate the potentially conserved role of epigenetic silencing in regulating stem cell behavior, we will test roles of Polycomb group transcriptional repression machinery, including PRC2 components and BmM homologs, as well as chromatin remodeling components, in stem or progenitor cell self-renewal, division or differentiation.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM080501-04S1
Application #
8111364
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Haynes, Susan R
Project Start
2010-08-06
Project End
2011-04-30
Budget Start
2010-08-06
Budget End
2011-04-30
Support Year
4
Fiscal Year
2010
Total Cost
$14,421
Indirect Cost
Name
Stanford University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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
Davies, Erin L; Lim, Jaclyn G Y; Joo, William J et al. (2013) The transcriptional regulator lola is required for stem cell maintenance and germ cell differentiation in the Drosophila testis. Dev Biol 373:310-21
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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