SHISA6 Confers Resistance to Differentiation-Promoting Wnt/β-Catenin Signaling in Mouse Spermatogenic Stem Cells

In the seminiferous tubules of mouse testes, a population of glial cell line-derived neurotrophic factor family receptor alpha 1 (GFR alpha 1)positive spermatogonia harbors the stem cell functionality and supports continual spermatogenesis, likely independent of asymmetric division or definitive niche control. Here, we show that activation of Wnt/beta-catenin signaling promotes spermatogonial differentiation and reduces the GFR alpha 1(+) cell pool. We further discovered that SHISA6 is a cell-autonomous Wnt inhibitor that is expressed in a restricted subset of GFRa1(+) cells and confers resistance to the Wnt/b-catenin signaling. Shisa6(+) cells appear to show stem cell-related characteristics, conjectured from the morphology and long-term fates of T (Brachyury)(+) cells that are found largely overlapped with Shisa6(+) cells. This study proposes a generic mechanism of stem cell regulation in a facultative (or open) niche environment, with which different levels of a cell-autonomous inhibitor (SHISA6, in this case) generates heterogeneous resistance to widely distributed differentiation-promoting extracellular signaling, such as WNTs.