There is intense interest in the circuits that guide stem cell behavior. In many of our tissues, these stem cell regulatory circuits are controlled by the niches that house the stem cells. it is not understood how the niche is specified and assembled in a tissue, and then how it executes control over the stem cell pool. Understanding these interactions will be crucial to the use of stem cells in regenerative medicine. This proposal utilizes one of the most well-understood stem cell-niche systems, the Drosophila testis. Here, a small group of cells (hub cells) act as part of the niche, leading to the activation of signaling pathways in adjacent cells. In this way, nearby somatic cells take on cyst stem cell fate (CySC), while nearby germline cells, intermingled with these CySCs, take on germline stem cell fate (GSC). Importantly, these two distinct stem cell types must coordinate their production of daughter cells for spermatogenesis to occur properly. Over the last funding cycle, we made fundamental breakthroughs in live- imaging both niche assembly and niche function. Here, we capitalize on this unprecedented level of resolution to tackle the mechanisms that underlie niche assembly and function. Hub formation, and the attendant attachment of stem cells, is the major architectural event of gonadogenesis. The specification and placement of hub cells among somatic gonadal precursors (SGPs) generates an anteriorly-anchored proliferation center that will drive spermatogenesis in a polarized manner. To generate that polarity, a subset of pre-hub cells must respond to positioning cues. However, neither those cues nor their source are currently known. This proposal seeks to define those cues and how they work. In many of our tissues, niches house multiple stem cell types, just as does the Drosophila testis niche. Thus, to maintain tissues the behavior of the multiple resident stem cell types must be coordinated. However, in no case do we understand how. This proposal will address this essential question.

Public Health Relevance

Potential implications for human health: There is intense interest in the circuits that guide stem cell behavior. Understanding niche-stem cell interactions is central to unraveling the circuitry necessary to use these cells in regenerative medicine. Thus, this proposal addresses these three conceptually significant facets of stem cell-niche biology: how are niches specified, organized and function.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM060804-18
Application #
9247208
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Haynes, Susan R
Project Start
1999-08-01
Project End
2020-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
18
Fiscal Year
2017
Total Cost
$369,244
Indirect Cost
$137,045
Name
University of Pennsylvania
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ly, Dan; Resch, Erin; Ordiway, George et al. (2017) Asymmetrically deployed actomyosin-based contractility generates a boundary between developing leg segments in Drosophila. Dev Biol 429:165-176
Wingert, Lindsey; DiNardo, Stephen (2015) Traffic jam functions in a branched pathway from Notch activation to niche cell fate. Development 142:2268-77
Lenhart, Kari F; DiNardo, Stephen (2015) Somatic cell encystment promotes abscission in germline stem cells following a regulated block in cytokinesis. Dev Cell 34:192-205
Dinardo, Stephen; Okegbe, Tishina; Wingert, Lindsey et al. (2011) lines and bowl affect the specification of cyst stem cells and niche cells in the Drosophila testis. Development 138:1687-96
Okegbe, Tishina C; DiNardo, Stephen (2011) The endoderm specifies the mesodermal niche for the germline in Drosophila via Delta-Notch signaling. Development 138:1259-67
Zheng, Qi; Wang, Yiwen; Vargas, Eric et al. (2011) magu is required for germline stem cell self-renewal through BMP signaling in the Drosophila testis. Dev Biol 357:202-10
Leatherman, Judith L; Dinardo, Stephen (2010) Germline self-renewal requires cyst stem cells and stat regulates niche adhesion in Drosophila testes. Nat Cell Biol 12:806-11
Leatherman, Judith L; Dinardo, Stephen (2008) Zfh-1 controls somatic stem cell self-renewal in the Drosophila testis and nonautonomously influences germline stem cell self-renewal. Cell Stem Cell 3:44-54
Franklin-Dumont, Tina M; Chatterjee, Chandrima; Wasserman, Steven A et al. (2007) A novel eIF4G homolog, Off-schedule, couples translational control to meiosis and differentiation in Drosophila spermatocytes. Development 134:2851-61
Wallenfang, Matthew R; Nayak, Renuka; DiNardo, Stephen (2006) Dynamics of the male germline stem cell population during aging of Drosophila melanogaster. Aging Cell 5:297-304

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