Tcf3 Governs Stem Cell Features and Represses Cell Fate Determination in Skin

Howard Hughes Medical Institute, Department of Mammalian Cell Biology and Development, The Rockefeller University, 1230 York Avenue, Box 300, New York, NY 10021, USA.
Cell (Impact Factor: 32.24). 11/2006; 127(1):171-83. DOI: 10.1016/j.cell.2006.07.036
Source: PubMed


Many stem cells (SCs) respond to Wnt signaling, but whether beta-catenin's DNA binding partners, the Tcfs, play a role in SCs in the absence of Wnts, is unknown. In adult skin, quiescent multipotent progenitors express Tcf3 and commit to a hair cell fate in response to Wnt signaling. We find that embryonic skin progenitors also express Tcf3. Using an inducible system in mice, we show that upon Tcf3 reactivation, committed epidermal cells induce genes associated with an undifferentiated, Wnt-inhibited state and Tcf3 promotes a transcriptional program shared by embryonic and postnatal SCs. Further, Tcf3-repressed genes include transcriptional regulators of the epidermal, sebaceous gland and hair follicle differentiation programs, and correspondingly, all three terminal differentiation pathways are suppressed when Tcf3 is induced postnatally. These data suggest that in the absence of Wnt signals, Tcf3 may function in skin SCs to maintain an undifferentiated state and, through Wnt signaling, directs these cells along the hair lineage.

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    • "Distinct hair cycle stages were judged as previously described (Muller- Rover et al., 2001; Greco et al., 2009; Oshimori and Fuchs, 2012). Hematoxylin and Eosin (H&E) staining and immunofluorescence were performed as previously described (Nguyen et al., 2006; Hu et al., 2012; Oshimori and Fuchs, 2012). Back skins from mice were embedded and frozen in OCT (Tissue Tek). "
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    ABSTRACT: Hair follicles (HFs) undergo cycles of degeneration (catagen), rest (telogen), and regeneration (anagen) phases. Anagen begins when the hair follicle stem cells (HFSCs) obtain sufficient activation cues to overcome suppressive signals mainly through the BMP pathway from their niche cells. Here, we unveil that mTOR complex 1 (mTORC1) signaling is activated in HFSCs, which coincides with the HFSC activation at the telogen-to-anagen transition. By using both an inducible conditional gene targeting strategy and a pharmacological inhibition method to ablate or inhibit mTOR signaling in adult skin epithelium before anagen initiation, we demonstrate that HFs that cannot respond to mTOR signaling display significantly delayed HFSC activation and extended telogen. Unexpectedly, BMP signaling activity is dramatically prolonged in mTOR signaling-deficient HFs. Through both gain- and loss-of-function studies in vitro, we show that mTORC1 signaling negatively affects BMP signaling, which serves as a main mechanism whereby mTORC1 signaling facilitates HFSC activation. Indeed, in vivo suppression of BMP by its antagonist Noggin rescues the HFSC activation defect in mTORC1-null skin. Our findings reveal a critical role for mTOR signaling in regulating stem cell activation through counterbalancing BMP-mediated repression during hair regeneration. © The Author (2015). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.
    Journal of Molecular Cell Biology 01/2015; DOI:10.1093/jmcb/mjv005 · 6.77 Impact Factor
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    • "All experiments were approved by the Cincinnati Children's Hospital Research Foundation Institutional Animal Care and Use Committee and were carried out using standard procedures. Genotyping was conducted by PCR of tail skin DNA using mouse Cre, Tgfbr2, EYFP, K14-rtTA and TRE2-Spdef primers, as described previously (Soriano, 1999; Nguyen et al., 2006; Guasch et al., 2007; Park et al., 2007). "
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    Development 11/2014; 141(23). DOI:10.1242/dev.117804 · 6.46 Impact Factor
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    • "Intriguingly, Tcf3 was found to be expressed in different types of stem cells including embryonic and hair follicle stem cells. Whereas Tcf3 promotes differentiation of ES cells, in part through counteracting Wnt-mediated maintenance signals, it promotes the maintenance of hair follicle stem cells, in part through counteracting Wnt-mediated epidermal differentiation [26], [27]. A recent study reported that Tcf3 is also expressed in the neocortical VZ and that Tcf3 overexpression suppresses and knockdown promotes neuronal differentiation of neocortical NPCs [28]. "
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