Kindlin-1 controls Wnt and TGF-β availability to regulate cutaneous stem cell proliferation

Abstract

Kindlin-1 is an integrin tail binding protein that controls integrin activation. Mutations in the FERMT-1 gene, which encodes for Kindlin-1, lead to Kindler syndrome in man, which is characterized by skin blistering, premature skin aging and skin cancer of unknown etiology. Here we show that loss of Kindlin-1 in mouse keratinocytes recapitulates Kindler syndrome and also produces enlarged and hyperactive stem cell compartments, which lead to hyperthickened epidermis, ectopic hair follicle development and increased skin tumor susceptibility. Mechanistically, Kindlin-1 controls keratinocyte adhesion through β1-class integrins and proliferation and differentiation of cutaneous epithelial stem cells by promoting αvβ6 integrin–mediated transforming growth factor-β (TGF-β) activation and inhibiting Wnt–β-catenin signaling through integrin-independent regulation of Wnt ligand expression. Our findings assign Kindlin-1 the previously unknown and essential task of controlling cutaneous epithelial stem cell homeostasis by balancing TGF-β–mediated growth-inhibitory signals and Wnt–β-catenin–mediated growth-promoting signals.

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Figure 1: Kindlin-1 controls HF growth.
Figure 2: Premature anagen induction and ectopic HF development in skin from Kind1-K5 mice.
Figure 3: Kindlin-1 regulates cutaneous epithelial SC homeostasis.
Figure 4: Kindlin-1 promotes αvβ6 integrin–induced TGF-β release in vitro and in vivo.
Figure 5: Kindlin-1 controls Wnt–β-catenin signaling.
Figure 6: Loss of Kindlin-1 increases skin tumor incidence.

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Acknowledgements

We thank J. Polleux for generating gold nanoarrays, S. Bach for expert technical assistance, C. Mein (Barts and the London Genome Centre) for generating the human microarray data and R. Zent and R. Paus for carefully reading the manuscript. We thank M. Aumailley (University of Cologne), R. Grosschedl (Max Planck Institute (MPI) Immunobiology), S. Violette (Biogen Idec), D. Sheppard (University of California, San Francisco) and M. Wegner (University of Erlangen) for providing antibodies and I. Thesleff (University of Helsinki), R. Kageyama (Kyoto University), A. Kispert (University of Hannover) and J. Behrens (University of Erlangen) for sending essential constructs. This work was funded by the US National Institutes of Health (CA034282) to D.B.R., the Wellcome Trust (PhD studentship to J.E.L.-C.) and the UK National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St. Thomas' National Health Service Foundation Trust and King's College London to J.A.M., the Advanced European Research Council (ERC) Grant (ERC Grant Agreement 322652) and the Max Planck Society to R.F.

Author information

R.F. initiated the project. R.F. and E.R. designed the experiments and wrote the paper. E.R., D.K., M.W., M.J., R.R., S.U., R.T.B. and J.E.L.-C. performed experiments. E.R., M.W., M.J. and R.F. analyzed data. D.B.R. and J.A.M. provided important reagents and/or analytical tools. All authors read and approved the manuscript.

Correspondence to Reinhard Fässler.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 and Supplementary Tables 1, 3 and 4. (PDF 23014 kb)

Supplementary Table 2

Microarray data with significant gene expression changes of 2 fold. First sheet shows all genes sorted by the difference score. In the following sheets genes are divided in the indicated categories (Wnt signaling; Inflammation and Wound healing; Proliferation and Cell cycle; Metabolism). N, NHS skin; K, KS skin; AVG, average; DiffScor, difference score. (XLSX 126 kb)

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Rognoni, E., Widmaier, M., Jakobson, M. et al. Kindlin-1 controls Wnt and TGF-β availability to regulate cutaneous stem cell proliferation. Nat Med 20, 350–359 (2014). https://doi.org/10.1038/nm.3490

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