There is intense interest in the circuits that guide stem cell behavior. While niches are essential to the behavior of many tissue-specific 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 use these cells in regenerative medicine. This proposal addresses how are niches specified, organized and function, and 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 t 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). 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 migrates through the germ cell milieu of the forming gonad, and undergoes a mesenchymal-to-epithelial transition (MET), only then acting as niche cells. Finally, the key self-renewal signal is delivered by BMPs expressed from both hub cells and CySCs.
The first Aim uses a combination of live-imaging and loss- and gain-of-function studies to explore cytoskeletal control of pre-hub cell migration, and the mesenchymal-to-epithelial transition necessary for niche formation.
A second Aim focuses on Zfh1, a transcriptional regulator which is key to CySC self- renewal and to how CySCs act as niche cells for GSC renewal. Targets of Zfh1 will be indentified and analyzed functionally. This will define genes important for CySC self- renewal, for the production of renewal signals for GSCs, and for the control of MET.
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.
|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|
|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|
|Terry, Natalie A; Tulina, Natalia; Matunis, Erika et al. (2006) Novel regulators revealed by profiling Drosophila testis stem cells within their niche. Dev Biol 294:246-57|
|Kauffman, Tate; Tran, John; DiNardo, Stephen (2003) Mutations in Nop60B, the Drosophila homolog of human dyskeratosis congenita 1, affect the maintenance of the germ-line stem cell lineage during spermatogenesis. Dev Biol 253:189-99|
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