title: Axin2 marks quiescent hair follicle bulge stem cells that are maintained by autocrine Wnt/β-catenin signaling.
abstract: How stem cells maintain their identity and potency as tissues change during growth is not well understood. In mammalian hair, it is unclear how hair follicle stem cells can enter an extended period of quiescence during the resting phase but retain stem cell potential and be subsequently activated for growth. Here, we use lineage tracing and gene expression mapping to show that the Wnt target gene Axin2 is constantly expressed throughout the hair cycle quiescent phase in outer bulge stem cells that produce their own Wnt signals. Ablating Wnt signaling in the bulge cells causes them to lose their stem cell potency to contribute to hair growth and undergo premature differentiation instead. Bulge cells express secreted Wnt inhibitors, including Dickkopf (Dkk) and secreted frizzled-related protein 1 (Sfrp1). However, the Dickkopf 3 (Dkk3) protein becomes localized to the Wnt-inactive inner bulge that contains differentiated cells. We find that Axin2 expression remains confined to the outer bulge, whereas Dkk3 continues to be localized to the inner bulge during the hair cycle growth phase. Our data suggest that autocrine Wnt signaling in the outer bulge maintains stem cell potency throughout hair cycle quiescence and growth, whereas paracrine Wnt inhibition of inner bulge cells reinforces differentiation.
authors.affiliation: Institute of Medical Biology, Agency for Science, Technology, and Research, Singapore 138648; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 639798; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305-5329; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305-5329; Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore 169857; xinhong.lim@imb.a-star.edu.sg rnusse@stanford.edu.
authors.forename: Xinhong
authors.initials: X
authors.lastname: Lim
authors.affiliation: Institute of Medical Biology, Agency for Science, Technology, and Research, Singapore 138648; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305-5329; Cancer Biology Program, Stanford University School of Medicine, Stanford, CA 94305-5329.
authors.forename: Si Hui
authors.initials: SH
authors.lastname: Tan
authors.affiliation: Institute of Medical Biology, Agency for Science, Technology, and Research, Singapore 138648;
authors.forename: Ka Lou
authors.initials: KL
authors.lastname: Yu
authors.affiliation: Institute of Medical Biology, Agency for Science, Technology, and Research, Singapore 138648;
authors.forename: Sophia Beng Hui
authors.initials: SB
authors.lastname: Lim
authors.affiliation: Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305-5329; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305-5329; xinhong.lim@imb.a-star.edu.sg rnusse@stanford.edu.
authors.forename: Roeland
authors.initials: R
authors.lastname: Nusse
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019898:Autocrine Communication; D060466:Axin Protein / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D018859:Hair Follicle / Q000166:cytology* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D060466:Axin Protein; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051153:Wnt Proteins; D051176:beta Catenin; C111729:Axin2 protein, mouse; C495267:CTNNB1 protein, mouse; C405061:Dkk3 protein, mouse; C485539:Sfrp1 protein, mouse; D000094742:Secreted Frizzled-Related Proteins
keywords: Wnt signaling; hair follicle; homeostasis; regeneration; stem cells