title: SHISA6 Confers Resistance to Differentiation-Promoting Wnt/β-Catenin Signaling in Mouse Spermatogenic Stem Cells.
abstract: 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.
authors.affiliation: Division of Germ Cell Biology, National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki 444-8787, Japan; Department of Basic Biology, School of Life Science, Graduate University for Advanced Studies (Sokendai), Okazaki 444-8585, Japan.
authors.forename: Moe
authors.initials: M
authors.lastname: Tokue
authors.affiliation: Division of Germ Cell Biology, National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki 444-8787, Japan; Department of Basic Biology, School of Life Science, Graduate University for Advanced Studies (Sokendai), Okazaki 444-8585, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Ikami
authors.affiliation: Laborarory Animal Resource Center, University of Tsukuba, Tsukuba 305-8575, Japan.
authors.forename: Seiya
authors.initials: S
authors.lastname: Mizuno
authors.affiliation: Division of Morphogenesis, National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki 444-8585, Japan.
authors.forename: Chiyo
authors.initials: C
authors.lastname: Takagi
authors.affiliation: Division of Morphogenesis, National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki 444-8585, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Miyagi
authors.affiliation: Division of Molecular and Developmental Biology, National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki 444-8787, Japan; Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, Okazaki 444-8787, Japan.
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Takada
authors.affiliation: Division of Developmental Genetics, National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki 444-8787, Japan.
authors.forename: Chiyo
authors.initials: C
authors.lastname: Noda
authors.affiliation: Division of Germ Cell Biology, National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki 444-8787, Japan; Department of Basic Biology, School of Life Science, Graduate University for Advanced Studies (Sokendai), Okazaki 444-8585, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Kitadate
authors.affiliation: Division of Germ Cell Biology, National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki 444-8787, Japan; Department of Basic Biology, School of Life Science, Graduate University for Advanced Studies (Sokendai), Okazaki 444-8585, Japan; Laboratory of Animal Reproduction and Development, Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555, Japan.
authors.forename: Kenshiro
authors.initials: K
authors.lastname: Hara
authors.affiliation: Division of Germ Cell Biology, National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki 444-8787, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Mizuguchi
authors.affiliation: Laboratory of Proteomics, Institute of Molecular Medicine and Life Science, Yokohama City University Association of Medical Science, Yokohama 236-0004, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Sato
authors.affiliation: Division of Experimental Therapeutics Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Makoto Mark
authors.initials: MM
authors.lastname: Taketo
authors.affiliation: Laborarory Animal Resource Center, University of Tsukuba, Tsukuba 305-8575, Japan.
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Sugiyama
authors.affiliation: Laboratory of Proteomics, Institute of Molecular Medicine and Life Science, Yokohama City University Association of Medical Science, Yokohama 236-0004, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Ogawa
authors.affiliation: Department of Basic Biology, School of Life Science, Graduate University for Advanced Studies (Sokendai), Okazaki 444-8585, Japan; Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, Okazaki 444-8787, Japan; Division of Developmental Genetics, National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki 444-8787, Japan; Life Science Center of Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba 305-8577, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Kobayashi
authors.affiliation: Department of Basic Biology, School of Life Science, Graduate University for Advanced Studies (Sokendai), Okazaki 444-8585, Japan; Division of Morphogenesis, National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki 444-8585, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Ueno
authors.affiliation: Laborarory Animal Resource Center, University of Tsukuba, Tsukuba 305-8575, Japan; Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Department of Basic Biology, School of Life Science, Graduate University for Advanced Studies (Sokendai), Okazaki 444-8585, Japan; Division of Molecular and Developmental Biology, National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki 444-8787, Japan; Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, Okazaki 444-8787, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Takada
authors.affiliation: Division of Germ Cell Biology, National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki 444-8787, Japan; Department of Basic Biology, School of Life Science, Graduate University for Advanced Studies (Sokendai), Okazaki 444-8585, Japan. Electronic address: shosei@nibb.ac.jp.
authors.forename: Shosei
authors.initials: S
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation; D015870:Gene Expression; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012671:Seminiferous Tubules / Q000378:metabolism; D013091:Spermatogenesis / Q000235:genetics; D013093:Spermatogonia / Q000166:cytology* / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics; D060449:Wnt Signaling Pathway
chemical_list: C494988:Gfra1 protein, mouse; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C514669:Shisa protein, mouse; D051153:Wnt Proteins; C095936:Wnt6 protein, mouse
keywords: Shisa6; Wnt/β-catenin inhibitor; differentiation; mouse spermatogenesis; stem cell