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: 33.12). 11/2006; 127(1):171-83. DOI: 10.1016/j.cell.2006.07.036
Source: PubMed

ABSTRACT 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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Available from: Michael Rendl, Sep 04, 2015
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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 · 8.43 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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    ABSTRACT: During mouse neocortical development, the Wnt-β-catenin signaling pathway plays essential roles in various phenomena including neuronal differentiation and proliferation of neural precursor cells (NPCs). Production of the appropriate number of neurons without depletion of the NPC population requires precise regulation of the balance between differentiation and maintenance of NPCs. However, the mechanism that suppresses Wnt signaling to prevent premature neuronal differentiation of NPCs is poorly understood. We now show that the HMG box transcription factor Tcf3 (also known as Tcf7l1) contributes to this mechanism. Tcf3 is highly expressed in undifferentiated NPCs in the mouse neocortex, and its expression is reduced in intermediate neuronal progenitors (INPs) committed to the neuronal fate. We found Tcf3 to be a repressor of Wnt signaling in neocortical NPCs in a reporter gene assay. Tcf3 bound to the promoter of the proneural bHLH gene Neurogenin1 (Neurog1) and repressed its expression. Consistent with this, Tcf3 repressed neuronal differentiation and increased the self-renewal activity of NPCs. We also found that Wnt signal stimulation reduces the level of Tcf3, and increases those of Tcf1 (also known as Tcf7) and Lef1, positive mediators of Wnt signaling, in NPCs. Together, these results suggest that Tcf3 antagonizes Wnt signaling in NPCs, thereby maintaining their undifferentiated state in the neocortex and that Wnt signaling promotes the transition from Tcf3-mediated repression to Tcf1/Lef1-mediated enhancement of Wnt signaling, constituting a positive feedback loop that facilitates neuronal differentiation.
    PLoS ONE 05/2014; 9(5):e94408. DOI:10.1371/journal.pone.0094408 · 3.23 Impact Factor
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    • "For example, β-catenin-deficient stem cells fail to differentiate into follicular keratinocytes and instead adopt an epidermal fate 12. Nguyen et al. found that Tcf3 might function to direct embryonic skin progenitors along their hair fate. Their subsequent work discovered that coexpress of Tcf3 and Tcf4 was response for long-term maintenance and wound repair of both epidermis and hair follicles 13,14. Recently, the presence and localization of Lef-1 in murine hair follicles during the first hair cycle were investigated 15, but the mechanism of this process is still under study. "
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    ABSTRACT: Lymphoid enhancer binding factor-1 (Lef1) is an essential regulatory protein in the Wnt signal pathway, which controls cell growth and differentiation. Investigators in the field of skin biology have confirmed that multipotent bulge stem cells (BSCs) are responsible for hair follicle development and regeneration. However, the role of Lef1 remains poorly understood. In this study, we investigated the pattern of Lef1 expression at different stages of the hair growth cycle. Lef1 was strongly expressed during anagen but attenuated in both catagen- and telogen-phase hair follicles in vivo. When stem cells were induced to differentiate toward a hair fate in a co-culture system, Lef1 was notably up-regulated and accumulated in the nucleus, appearing to activate the target protein c-myc and jagged1. Simultaneously, the Wnt and Notch signaling pathways were co-activated, as confirmed by the increased expression of β-catenin and notch1. Plasmids expressing Lef1 and ΔNLef1, a construct in which the β-catenin-binding domain of Lef1 was deleted, were used to evaluate the effects of Lef1 on stem cell differentiation. Lef1 overexpression promoted bulge stem cell differentiation toward a hair fate, which was accompanied by the subsequent migration of β-catenin into the nucleus, whereas no changes were observed in the control group. Taken together, our results demonstrate that Lef1 plays an important role in bulge stem cell differentiation, promoting β-catenin translocation into the nucleus, activating downstream signaling molecules, eventually causing hair follicle bulge stem cells to adopt the hair fate.
    International journal of medical sciences 04/2013; 10(6):738-46. DOI:10.7150/ijms.5693 · 1.55 Impact Factor
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