Department of Cell Biology
263 Farmington Avenue
Farmington, CT 06030
Regulation Niche-Stem Cell Interaction
Adult tissue stem cells produce highly differentiated but short-lived cells throughout life, contributing to the tissue maintenance and repair. Specialized environments called “niches” help to maintain stem cells by producing signals essential for stem cell maintenance. Stem cell-niche signaling has to be carefully regulated, since an excess of signal activation can lead to tumorigenic overproliferation of stem cells, while its shortage can deplete stem cells, causing tissue degeneration. Thus, niche signal has to meet two criteria 1) sufficient signal activation in stem cells, 2) no (or lower than threshold) signal activation in non-stem cells. Stem cells and their non-stem cell daughters are often juxtaposed each other, and thus how specificity of spatially confined niche signaling is achieved has been a mystery. It has been postulated that the secreted niche ligands “diffuse” only in a short-range, but how the range of diffusion can be tightly regulated remained unknown. We recently discovered previously unrecognized cellular protrusions, termed MT (microtubule-based)-nanotubes, that are specifically formed by stem cells and extend into the hub cells, the major niche component in the Drosophila testis. Our preliminary studies indicate that MT-nanotubes promote BMP signaling (Dpp ligand-Tkv receptor), a niche ligand required for stem cell maintenance. Based on our preliminary studies, we hypothesize that MT-nanotubes function to mediate productive niche signaling such that only stem cells experience enough niche-dependent signal transduction, providing a mechanistic basis for the short-range nature of the niche signaling. We further explore molecular and cellular mechanisms of MT-nanotube-mediated niche-stem cell signaling as outlined below.
Elucidate the mechanisms of MT-nanotube-mediated signaling: Our preliminary study revealed that MT-nanotubes promote Dpp signaling in GSCs. However, the molecular mechanism by which MT-nanotubes promote signal activation remains unknown. We design the tools for time-lapse observation of signaling machinery and visualize the behavior of signaling molecules as well as downstream signaling outcome.
Investigate the mechanism by which MT-nanotubes achieve selective signal transduction: Two hub ligands Unpaired (Upd) and Dpp signals are known to activate the downstream self-renewal pathways in GSCs. GSCs utilize MT-nanotubes for Dpp but not for Upd. We will investigate how MT-nanotubes selectively contribute to the regulation of Dpp signaling but not Upd-JAK-STAT signaling.
Examine the presence and function of MT-nanotubes in other stem cell systems: We have found several other Drosophila stem cells also form MT-nanotube-like structure, suggesting that MT-nanotube-based mechanisms may promote spatially-confined signaling in a broad range of cell types. We will further examine the presence and function of MT-nanotubes in other cell types including different organisms.
Funding: NIGMS 1R35GM128678-01
Mayu Inaba, Dorothy R. Sorenson, Matt Kortus, Viktoria Salzmann, & Yukiko M. Yamashita. “Merlin is required for coordinating proliferation of two stem cell lineages in the Drosophila testis“. Scientific Reports 7: 2502, DOI:10.1038/s41598-017-02768-z. May 2017.
Cuie Chen, Mayu Inaba, Zsolt G Venkei, Yukiko M Yamashita. “Klp10A, a stem cell centrosome-enriched kinesin, balances asymmetries in Drosophila male germline stem cell division“. eLife 2016;5:e20977. http://dx.doi.org/10.7554/eLife.20977.
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