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The ability of adult organisms to maintain tissue homeostasis and repair tissue in response to injury is mediated by small groups of partially differentiated cells called adult stem cells that support the tissue they reside in. Adult stem cell maintenance is highly regulated by signals from the surrounding microenvironment referred to as the stem cell niche. A better understanding of this process will have important implications for the fields of both regenerative medicine and cancer biology. Due to the complexity of most niche environments in mammals, we turned to the less complex model organism Drosophila and the well-characterized niche in the testis. This niche contains multiple populations of cells that function in a stereotypical way. The Hub cells are most apical and form the foundation of the niche, the germline stem cells (GSCs) that ultimately produce sperm and the somatic cyst stem cells (CySCs) that guide the germline cells through differentiation both contact the hub. How these stem cells coordinate their proliferation with one another remains a mystery. Recently, contact inhibition, mediated by the tumor suppressor Merlin, was proposed as a mechanism to coordinate proliferation. In other Drosophila tissues, Merlin appears to act somewhat redundantly with the related tumor suppressor Expanded. The goals of this research were to discriminate the functional role of Merlin and Expanded in the cyst lineage of the testis niche. In this study, we investigated the possible downstream signaling mechanisms that Merlin may suppress by looking at three cellular pathways, EGFR, Rac1, and Akt/Tor, that are known to be regulated by Merlin in other tissues and have distinct functions in the Cyst lineage. We found that Merlin and Expanded cause cells in the cyst lineage to outcompete the germline stem cells for access to the niche. When Merlin was always active in its tumor suppressor role, we observed a similar phenotype to when Merlin was lost. These similarities in phenotype between loss and gain of function support a model where Merlin acts to balance multiple signaling inputs within the cyst lineage. Consistent with this, we observed increased MAPK signaling in the cyst linage when Merlin was lost, and a decrease in Tor signaling in constitutively activated Merlin, and that a balance between these pathways is needed for proper stem cell maintenance and proliferation.


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Available for download on Sunday, December 12, 2021