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Tcf3 and Tcf4 are essential for long-term homeostasis of skin epithelia

Nature Genetics volume 41, pages 1068–1075 (2009)Cite this article

Abstract

Single-layered embryonic skin either stratifies to form epidermis or responds to Wnt signaling (stabilized β-catenin) to form hair follicles. Postnatally, stem cells continue to differentially use Wnt signaling in long-term tissue homeostasis. We have discovered that embryonic progenitor cells and postnatal hair follicle stem cells coexpress Tcf3 and Tcf4, which can act as transcriptional activators or repressors. Using loss-of-function studies and transcriptional analyses, we uncovered consequences to the absence of Tcf3 and Tcf4 in skin that only partially overlap with those caused by β-catenin deficiency. We established roles for Tcf3 and Tcf4 in long-term maintenance and wound repair of both epidermis and hair follicles, suggesting that Tcf proteins have both Wnt-dependent and Wnt-independent roles in lineage determination.

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Figure 1: Tcf4 shares an expression pattern similar to that of Tcf3 in skin, where it becomes largely restricted to the slow-cycling hair follicle (bulge) stem cells and their early ORS progeny.
Figure 2: Sustained epidermal expression suggests repressor and activator functions for Tcf4.
Figure 3: Characterization of skin of newborn mice lacking Tcf3 and Tcf4.
Figure 4: Skin grafting permits evaluation of the long-term consequences of Tcf3 and Tcf4 ablation in skin.
Figure 5: Measuring the stem cell potential within hair follicles and epidermis in the absence of Tcf3 and Tcf4.
Figure 6: Loss of Tcf3 and Tcf4 results in inability of cultured epidermal keratinocytes to undergo long-term self-renewal.
Figure 7: Differences between Tcf3/4-null and Ctnnb1-null skin.
Figure 8: Ablation of Tcf3 and Tcf4 in skin leads to an upregulation of gene expression.

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Acknowledgements

We thank H. Clevers for providing Tcf4 knockout mice, Fuchs lab members for their help and critical discussions of the work and N. Stokes for assistance in the Comparative Biosciences Center animal facility at Rockefeller University. E.F. is an Investigator of the Howard Hughes Medical Institute. H.N. was the recipient of a Ruth Kirschstein postdoctoral fellowship from the National Institutes of Health. This work was supported by the Howard Hughes Medical Institute and a grant from the National Institutes of Health (R01-AR31737).

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Author notes

  1. Hoang Nguyen, Bradley J Merrill & Michael Rendl

    Present address: Present addresses: Department of Molecular and Cellular Biology & Stem Cell and Regenerative Medicine Center, Baylor College of Medicine, Houston, Texas, USA (H.N.); Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Illinois, USA (B.J.M.); and Department of Developmental and Regenerative Biology & Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, New York, USA (M.R.).,

Authors and Affiliations

  1. Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, New York, USA

    Hoang Nguyen, Bradley J Merrill, Lisa Polak, Maria Nikolova, Michael Rendl, H Amalia Pasolli & Elaine Fuchs

  2. Department of Molecular and Cellular Biology & Stem Cell and Regenerative Medicine Center, Baylor College of Medicine, Houston, Texas, USA

    Timothy M Shaver

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  1. Hoang Nguyen
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Contributions

H.N. designed and conducted experiments, analyzed data and wrote the paper. B.J.M. generated the Tcf3 cKO mice. M.R. conducted the microarray analysis. L.P. conducted the skin grafting. M.N. and T.M.S. provided technical assistance. H.A.P. conducted the histological analysis. E.F. designed experiments, analyzed data and wrote the paper. All authors read and contributed to the manuscript.

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Correspondence to Elaine Fuchs.

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Nguyen, H., Merrill, B., Polak, L. et al. Tcf3 and Tcf4 are essential for long-term homeostasis of skin epithelia. Nat Genet 41, 1068–1075 (2009). https://doi.org/10.1038/ng.431

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