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Klf4 is a transcription factor required for establishing the barrier function of the skin

Abstract

Located at the interface between body and environment, the epidermis must protect the body against toxic agents and dehydration, and protect itself against physical and mechanical stresses1,2,3,4. Acquired just before birth and at the last stage of epidermal differentiation, the skin's proteinaceous/lipid barrier creates a surface seal essential for protecting animals against microbial infections and dehydration. We show here that Kruppel-like factor 4 (Klf4, encoded by the gene Klf4), highly expressed in the differentiating layers of epidermis, is both vital to and selective for barrier acquisition. Klf4–/– mice die shortly after birth due to loss of skin barrier function, as measured by penetration of external dyes and rapid loss of body fluids. The defect was not corrected by grafting of Klf4–/– skin onto nude mice. Loss of the barrier occurs without morphological and biochemical alterations to the well-known structural features of epidermis that are essential for mechanical integrity. Instead, late-stage differentiation structures are selectively perturbed, including the cornified envelope, a likely scaffold for lipid organization. Using suppressive subtractive hybridization, we identified three transcripts encoding cornified envelope proteins with altered expression in the absence of Klf4. Sprr2a is one, and is the only epidermal gene whose promoter is known to possess a functional Klf4 binding site. Our studies provide new insights into transcriptional governance of barrier function, and pave the way for unravelling the molecular events that orchestrate this essential process.

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Figure 1: Klf4 expression and generation of mutant mice.
Figure 2: Barrier defects in Klf4–/– mice.
Figure 3: Aberrations in differentiation and CE formation in Klf4–/– stratified epithelia.
Figure 4: Ultrastructural abnormalities in Klf4–/– epidermis.
Figure 5: Differentially expressed genes in Klf4–/– mice.

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References

  1. Downing, D.T. Lipid and protein structures in the permeability barrier of mammalian epidermis. J. Lipid Res. 33, 301–313 (1992).

    CAS  PubMed  Google Scholar 

  2. Adams, J.C. & Watt, F.M. Regulation of development and differentiation by the extracellular matrix. Development 117, 1183–1198 (1993).

    CAS  PubMed  Google Scholar 

  3. Roop, D. Defects in the barrier. Science 267, 474–475 (1995).

    Article  CAS  Google Scholar 

  4. Fuchs, E. Keratins and the skin. Annu. Rev. Cell Dev. Biol. 11, 123–153 (1995).

    Article  CAS  Google Scholar 

  5. Shields, J.M., Christy, R.J. & Yang, V.W. Identification and characterization of a gene encoding a gut-enriched Kruppel-like factor expressed during growth arrest. J. Biol. Chem. 271, 20009–20017 (1996).

    Article  CAS  Google Scholar 

  6. Garrett-Sinha, L.A., Eberspaecher, H., Seldin, M.F. & de Crombrugghe, B. A gene for a novel zinc-finger protein expressed in differentiated epithelial cells and transiently in certain mesenchymal cells. J. Biol. Chem. 271, 31384–31390 (1996).

    Article  CAS  Google Scholar 

  7. Nuez, B., Michalovich, D., Bygrave, A., Ploemacher, R. & Grosveld, F. Defective haematopoiesis in fetal liver resulting from inactivation of the EKLF gene. Nature 375, 316–318 (1995).

    Article  CAS  Google Scholar 

  8. Perkins, A.C., Sharpe, A.H. & Orkin, S.H. Lethal β-thalassaemia in mice lacking the erythroid CACCC-transcription factor EKLF. Nature 375, 318–322 (1995).

    Article  CAS  Google Scholar 

  9. Kuo, C.T., Veselits, M.L. & Leiden, J.M. LKLF: a transcriptional regulator of single-positive T cell quiescence and survival. Science 277, 1986–1990 (1998).

    Article  Google Scholar 

  10. Hardman, M.J., Sisi, P., Banbury, D.N. & Byrne, C. Patterned acquisition of skin barrier function during development. Development 125, 1541–1552 (1998).

    CAS  PubMed  Google Scholar 

  11. Wickett, R.R., Nath, V., Tanaka, R. & Hoath, S.B. Use of continuous electrical capacitance and transepidermal water loss measurements for assessing barrier function in neonatal rat skin. Skin Pharmacol. 8, 179–185 (1995).

    Article  CAS  Google Scholar 

  12. Imakado, S. et al. Targeting expression of a dominant-negative retinoic acid receptor mutant in the epidermis of transgenic mice results in loss of barrier function. Genes Dev. 9, 317–329 (1995).

    Article  CAS  Google Scholar 

  13. Saitou, M. et al. Inhibition of skin development by targeted expression of a dominant-negative retinoic acid receptor. Nature 374, 159–162 (1995).

    Article  CAS  Google Scholar 

  14. Matsuki, M. et al. Defective stratum corneum and early neonatal death in mice lacking the gene for transglutaminase 1 (keratinocyte transglutaminase). Proc. Natl Acad. Sci. USA 95, 1044–1049 (1998).

    Article  CAS  Google Scholar 

  15. Yang, A. et al. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 398, 714–718 (1999).

    Article  CAS  Google Scholar 

  16. Mills, A.A. et al. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 398, 708–713 (1999).

    Article  CAS  Google Scholar 

  17. Takeda, K. et al. Limb and skin abnormalities in mice lacking IKKα. Science 284, 313–316 (1999).

    Article  CAS  Google Scholar 

  18. Hu, Y. et al. Abnormal morphogenesis but intact IKK activation in mice lacking the IKKα subunit of IκB kinase. Science 284, 316–320 (1999).

    Article  CAS  Google Scholar 

  19. Hohl, D. et al. Characterization of human loricrin. Structure and function of a new class of epidermal cell envelope proteins. J. Biol. Chem. 266, 6626–6636 (1991).

    CAS  PubMed  Google Scholar 

  20. Michel, S., Schmidt, R., Shroot, B. & Reichert, U. Morphological and biochemical characterization of the cornified envelopes from human epidermal keratinocytes of different origin. J. Invest. Dermatol. 91, 11–15 (1988).

    Article  CAS  Google Scholar 

  21. Steven, A.C., Bisher, M.E., Roop, D.R. & Steinert, P.M. Biosynthetic pathways of filaggrin and loricrin—two major proteins expressed by terminally differentiated epidermal keratinocytes. J. Struct. Biol. 140, 150–162 (1990).

    Article  Google Scholar 

  22. Steven, A.C. & Steinert, P.M. Protein composition of cornified cell envelopes of epidermal keratinocytes. J. Cell Sci. 107, 693–700 (1994).

    CAS  PubMed  Google Scholar 

  23. Hou, S.Y.E. et al. Membrane structures in normal and essential fatty acid-deficient stratum corneum: characterization by ruthenium tetroxide staining and X-ray diffraction. J. Invest. Dermatol. 96, 215–223 (1991).

    Article  CAS  Google Scholar 

  24. Fischer, D.F., Gibbs, S., van De Putte, P. & Backendorf, C. Interdependent transcription control elements regulate the expression of the SPRR2A gene during keratinocyte terminal differentiation. Mol. Cell. Biol. 16, 5365–5374 (1996).

    Article  CAS  Google Scholar 

  25. Yet, S.F. et al. Human EZF, a Kruppel-like zinc finger protein, is expressed in vascular endothelial cells and contains transcriptional activation and repression domains. J. Biol. Chem. 273, 1026–1031 (1998).

    Article  CAS  Google Scholar 

  26. Turner, J. & Crossley, M. Cloning and characterization of mCtBP2, a co-repressor that associates with basic Kruppel-like factor and other mammalian transcriptional regulators. EMBO J. 17, 5129–5140 (1998).

    Article  CAS  Google Scholar 

  27. Krieg, P. et al. Repetin (Rptn), a new member of the "fused gene" subgroup within the S100 gene family encoding a murine epidermal differentiation protein. Genomics 43, 339–348 (1997).

    Article  CAS  Google Scholar 

  28. Jensen, P.J., Wu, Q., Janowitz, P., Ando, Y. & Schechter, N.M. Plasminogen activator inhibitor type 2: an intracellular keratinocyte differentiation product that is incorporated into the cornified envelope. Exp. Cell Res. 217, 65–71 (1995).

    Article  CAS  Google Scholar 

  29. Song, H.J. et al. Mouse Sprr2 genes: a clustered family of genes showing differential expression in epithelial tissues. Genomics 55, 28–42 (1999).

    Article  CAS  Google Scholar 

  30. Schneider S.S. et al. A serine proteinase inhibitor locus at 18q21.3 contains a tandem duplication of the human squamous cell carcinoma antigen gene. Proc. Natl Acad. Sci. USA 92, 3147–3151 (1995).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank C. Copenhaver, M. Yin, A. Spektor, P. Zhou and L. Degenstein for assistance; I. Shapiro for use of the Nova DPM instrument; and C. Kuo, C. Byrne, A. Supp, S. Sinha and X. Dai for discussions and advice. J.A.S. is a Damon Runyon-Walter Winchell Foundation postdoctoral fellow, DRG-1413; E.F. is an Investigator of the Howard Hughes Medical Institute. This work was funded by a grant from The National Institutes of Health (AR31737).

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Correspondence to Elaine Fuchs.

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Segre, J., Bauer, C. & Fuchs, E. Klf4 is a transcription factor required for establishing the barrier function of the skin. Nat Genet 22, 356–360 (1999). https://doi.org/10.1038/11926

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