Although spermatogonial stem cells are essential for reproduction, their regulation is poorly understood. Environmental, genetic and epigenetic factors are crucial for stem cell establishment, maintenance, and function, but systematically identifying these factors is extremely challenging in mammalian systems. Consequently, the behavior of most stem cells within their natural tissue microenvironments, or niches, is not well-understood. However, understanding stem cell-niche interactions is critical for developing successful stem cell-based therapeutic approaches. We use Drosophila spermatogenesis as a model system, since it parallels mammalian systems, yet we can precisely locate the stem cells and manipulate their niche genetically. Prior funding enabled us to discover the molecular mechanism controlling stem cell renewal in the Drosophila testis. Stem cells adhere to a small cluster of somatic support cells called the hub, which secretes a ligand that activates Janus-kinase-signal transducer and activator of transcription (Jak-STAT) signaling in adjacent cells, instructing them to remain as stem cells. Daughters displaced away from the hub differentiate. Building on these findings, in this renewal we will characterize additional factors we have recently found to be required for stem cell maintenance in this niche, and determine if they act together with the Jak-STAT signaling pathway during this process. This includes using a combination of genetic and biochemical approaches to assess the role of 1) chromatin remodeling complexes and 2) hormonal signaling pathways in spermatogonial stem cell renewal. We will also identify additional genes regulated by Jak-STAT signaling then use genetic approaches to determine their roles in both normal and aged niches. Together this work will provide fundamental insight into the genetic and epigenetic mechanisms that regulate stem cell maintenance.

Public Health Relevance

This work will contribute significantly to what is known about the mechanisms regulating stem cells within an intact stem cell microenvironment (or niche) in vivo. Understanding how stem cells respond to niche signals is of fundamental importance for developing successful strategies to manipulate these potent cells in regenerative medicine.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD040307-12
Application #
8231299
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Moss, Stuart B
Project Start
2001-04-01
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
12
Fiscal Year
2012
Total Cost
$368,659
Indirect Cost
$143,867
Name
Johns Hopkins University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Stine, Rachel R; Greenspan, Leah J; Ramachandran, Kapil V et al. (2014) Coordinate regulation of stem cell competition by Slit-Robo and JAK-STAT signaling in the Drosophila testis. PLoS Genet 10:e1004713
Ma, Qing; Wawersik, Matthew; Matunis, Erika L (2014) The Jak-STAT target Chinmo prevents sex transformation of adult stem cells in the Drosophila testis niche. Dev Cell 31:474-86
Li, Yijie; Ma, Qing; Cherry, Christopher M et al. (2014) Steroid signaling promotes stem cell maintenance in the Drosophila testis. Dev Biol 394:129-41
Hétié, Phylis; de Cuevas, Margaret; Matunis, Erika (2014) Conversion of quiescent niche cells to somatic stem cells causes ectopic niche formation in the Drosophila testis. Cell Rep 7:715-21
Stine, Rachel R; Matunis, Erika L (2013) Stem cell competition: finding balance in the niche. Trends Cell Biol 23:357-64
Sheng, X Rebecca; Matunis, Erika (2011) Live imaging of the Drosophila spermatogonial stem cell niche reveals novel mechanisms regulating germline stem cell output. Development 138:3367-76
Issigonis, Melanie; Matunis, Erika (2011) SnapShot: stem cell niches of the Drosophila testis and ovary. Cell 145:994-994.e2
de Cuevas, Margaret; Matunis, Erika L (2011) The stem cell niche: lessons from the Drosophila testis. Development 138:2861-9
Cherry, Christopher M; Matunis, Erika L (2010) Epigenetic regulation of stem cell maintenance in the Drosophila testis via the nucleosome-remodeling factor NURF. Cell Stem Cell 6:557-67
Sheng, X Rebecca; Posenau, Trevor; Gumulak-Smith, Juliann J et al. (2009) Jak-STAT regulation of male germline stem cell establishment during Drosophila embryogenesis. Dev Biol 334:335-44

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