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 mechanisms that regulate self-renewal vs onset of differentiation in adult stem cell lineages are key for regenerative medicine as well as understanding the genesis and biology of cancer. We propose to investigate how interactions with somatic support cell partners regulate the decision between self renewal and differentiation in the Drosophila male germ line stem cell lineage, a powerful system for study of adult stem cells in vivo in the context of signals from their local environment. In previous funding cycles, w discovered that somatic cyst cells in the testis, functionally equivalent to mammalian Sertoli cells, provide a crucial microenvironment that regulates the switch from germ line stem cell to transit amplifying spermatogonia. We now propose to utilize the powerful system and tools we have established to investigate the molecular circuitry that regulates this key state transition in the male germ line stem cell lineage in response to cues from somatic support cells. To discover the intrinsic factors that maintain early germ cells in a state to either self-renew or initiate differentiation in response to their microenvironment, we will test models for transcriptional regulatory circuitry suggested from bioinformatic analysis of genes coordinately upregulated as germ line stem cells become TA spermatogonia, including the possible roles of the bHLH transcription factor Daughterless and its inhibitor Emc, and the Zn finger transcription factor Klu a regulator of stem cell state in neuroblast lineages, the repressor Aef-1, and the activator rotund. To elucidate whether and how cyst cells send a go differentiate signal to instruct germ line stem cells to exit self-renewal and enter the spermatogonial program of limited transit amplifying (TA) divisions, we will identify and investigate the role of genes encoding predicted secreted or cell surface proteins that are required in somatic cyst cells for early germ cells to properly initiate differentiation as transit amplifying spermatogonia, starting with Gp150, a regulator of Notch pathway signaling, identified in the initial rounds of our cell type specific RNi screen. Our results may elucidate an alternative view of the stem cell niche, in which differentiation signals play key roles, and will illuminate how close-range reciprocal cell-cell signaling can coordinate co-differentiation of disparate cell types that must work together to make functional tissues.

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 cells regulate proliferation and differentiation in adult stem cell lineages 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM080501-12
Application #
9616270
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Salazar, Desiree Lynn
Project Start
2007-05-01
Project End
2019-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
12
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Stanford University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
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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