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

Moe Tokue, Kanako Ikami, Seiya Mizuno, Chiyo Takagi, Asuka Miyagi, Ritsuko Takada, Chiyo Noda, Yu Kitadate, Kenshiro Hara, Hiroko Mizuguchi, Takuya Sato, Makoto Mark Taketo, Fumihiro Sugiyama, Takehiko Ogawa, Satoru Kobayashi, Naoto Ueno, Satoru Takahashi, Shinji Takada, Shosei Yoshida

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)


In the seminiferous tubules of mouse testes, a population of glial cell line-derived neurotrophic factor family receptor alpha 1 (GFRα1)-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/β-catenin signaling promotes spermatogonial differentiation and reduces the GFRα1+ cell pool. We further discovered that SHISA6 is a cell-autonomous Wnt inhibitor that is expressed in a restricted subset of GFRα1+ cells and confers resistance to the Wnt/β-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.

Original languageEnglish
Pages (from-to)561-575
Number of pages15
JournalStem Cell Reports
Issue number3
Publication statusPublished - 2017 Mar 14


  • Shisa6
  • Wnt/β-catenin inhibitor
  • differentiation
  • mouse spermatogenesis
  • stem cell

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology


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