Although spermatogonial stem cells are essential for reproduction, little is known about their regulation. Environmental and intrinsic factors are crucial for stem cell establishment and maintenance, but systematically identifying these factors is extremely challenging in mammalian systems. We use Drosophila spermatogenesis as a model system, since it parallels mammalian systems, yet we can precisely locate the stem cells, and manipulate their microenvironment genetically. Prior funding enabled us to discover the molecular mechanism controlling Drosophila spermatogonial stem cell self-renewal. Germline stem cells (GSCs) are anchored around a cluster of somatic support cells called the hub. The hub produces a ligand that activates Jak-Stat in adjacent germ cells, instructing them to remain as stem cells. Daughters displaced away from the hub differentiate. Building on preliminary data derived from these findings, in this renewal we address three fundamental questions.
In Aim 1, we pursue our preliminary data suggesting that Jak-Stat signaling converts GSC precursors (primordial germ cells) into GSCs by characterizing germ cell behavior and Jak-Stat activity in the embryonic testis, then using genetics to determine the role of this pathway in GSC establishment.
In Aim 2, we extend our studies of Jak-Stat signaling in adult stem cells. Although GSCs require direct activation of Stat, this was not tested for SSCs.
In Aim 2 a, we determine if Jak-Stat signaling is directly or indirectly required for GSC maintenance.
In Aim 2 b, we pursue our extensive preliminary data indicating that socs36E, a target and inhibitor of Jak-Stat signaling, maintains GSCs in the testis. We will complete the characterization of our socs36E alleles, then we will determine if socs36E is directly or indirectly required for GSC maintenance. Finally, since targets of Stat in GSCs (& possibly SSCs) may be intrinsic determinants of stem cell fate, while targets in hub cells may regulate hub cell function, we will identify these targets, and test them for roles in stem cell maintenance using genetic approaches in Aim 3. Together this work will provide fundamental insight into the molecular mechanisms that regulate stem cell establishment and maintenance, which is of great importance towards developing potential therapeutic uses of stem 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 #
5R01HD040307-07
Application #
7149970
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Rankin, Tracy L
Project Start
2001-04-01
Project End
2009-11-30
Budget Start
2006-12-01
Budget End
2007-11-30
Support Year
7
Fiscal Year
2007
Total Cost
$335,253
Indirect Cost
Name
Johns Hopkins University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Ma, Qing; de Cuevas, Margaret; Matunis, Erika L (2016) Chinmo is sufficient to induce male fate in somatic cells of the adult Drosophila ovary. Development 143:754-63
Hasan, Salman; Hétié, Phylis; Matunis, Erika L (2015) Niche signaling promotes stem cell survival in the Drosophila testis via the JAK-STAT target DIAP1. Dev Biol 404:27-39
Greenspan, Leah Joy; de Cuevas, Margaret; Matunis, Erika (2015) Genetics of gonadal stem cell renewal. Annu Rev Cell Dev Biol 31:291-315
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) JAK-STAT signaling in stem cells. Adv Exp Med Biol 786:247-67
Stine, Rachel R; Matunis, Erika L (2013) Stem cell competition: finding balance in the niche. Trends Cell Biol 23:357-64
Sinden, D; Badgett, M; Fry, J et al. (2012) Jak-STAT regulation of cyst stem cell development in the Drosophila testis. Dev Biol 372:5-16

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