Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mechanisms of epithelial fusion and repair

Abstract

One of the principal functions of any epithelium in the embryonic or adult organism is to act as a self-sealing barrier layer. From the earliest stages of development, embryonic epithelia are required to close naturally occurring holes and to fuse wherever two free edges are brought together, and at the simplest level that is precisely what the epidermis must do to repair itself wherever it is damaged. Parallels can be drawn between the artificially triggered epithelial movements of wound repair and the naturally occurring epithelial movements that shape the embryo during morphogenesis. Recent in vitro and in vivo wound-healing studies and analysis of paradigm morphogenetic movements in genetically tractable embryos, like those of Drosophila and Caenorhabditis elegans, have begun to identify both the signals that initiate these movements and the cytoskeletal machinery that drives motility. We are also gaining insight into the nature of the brakes and stop signals, and the mechanisms by which the confronting epithelial sheets knit together to form a seam.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Lamellipodial crawling versus purse-string closure of an epithelial wound.
Figure 2: Cell-shape changes and shuffling occurring during repair of an epithelial tissue culture wound.
Figure 3: Parallels between wound repair and morphogenetic movements.
Figure 4: Filopodial priming as part of the epithelial adhesion machinery.
Figure 5: Filopodia may act as 'sensors' for leading-edge epithelial cells, as they do in axonal growth cones.
Figure 6: Keratin 6 is expressed by wound-edge keratinocytes and at sites of fetal epithelial fusion.

Similar content being viewed by others

References

  1. Woodley, D. T. in The Molecular and Cellular Biology of Wound Repair (ed. Clark, R. A. F.) 339–354 (Plenum, New York, 1996).

    Google Scholar 

  2. Martin, P. & Lewis, J. Actin cables and epidermal movement in embryonic wound healing. Nature 360, 179–183 (1992).

    Article  CAS  Google Scholar 

  3. McCluskey, J., Hopkinson-Woolley, J., Luke, B. & Martin, P. A study of wound healing in the E11.5 mouse embryo by light and electron microscopy. Tissue Cell 25, 173–181 (1993).

    Article  CAS  Google Scholar 

  4. Heath, J. P. Epithelial cell migration in the intestine. Cell Biol. Int. 20, 139–146 (1996).

    Article  CAS  Google Scholar 

  5. Danjo, Y. & Gipson, I. K. Actin 'purse string' filaments are anchored by E-cadherin-mediated adherens junctions at the leading edge of the epithelial wound, providing coordinated cell movement. J. Cell Sci. 111, 3323–3332 (1998).

    CAS  Google Scholar 

  6. Bement, W. M., Forscher, P. & Mooseker, M. S. A novel cytoskeletal structure involved in purse string wound closure and cell polarity maintenance. J. Cell Biol. 121, 565–578 (1993).

    Article  CAS  Google Scholar 

  7. Brock, J., Midwinter, K., Lewis, J. & Martin, P. Healing of incisional wounds in the embryonic chick wing bud: characterization of the actin purse-string and demonstration of a requirement for Rho activation. J. Cell Biol. 135, 1097–1107 (1996).

    Article  CAS  Google Scholar 

  8. Ridley, A. J. & Hall, A. The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell 70, 389–399 (1992).

    Article  CAS  Google Scholar 

  9. Fenteany, G., Janmey, P. A. & Stossel, T. P. Signaling pathways and cell mechanics involved in wound closure by epithelial cell sheets. Curr. Biol. 10, 831–838 (2000).

    Article  CAS  Google Scholar 

  10. Nobes, C. D. & Hall, A. Rho GTPases control polarity, protrusion, and adhesion during cell movement. J. Cell Biol. 144, 1235–1244 (1999).

    Article  CAS  Google Scholar 

  11. Fox, P. L., Sa, G., Dobrowolski, S. F. & Stacey, D. W. The regulation of endothelial cell motility by p21 ras. Oncogene 9, 3519–3526 (1994).

    CAS  Google Scholar 

  12. Garlick, J. A. & Taichman, L. B. Fate of human keratinocytes during reepithelialization in an organotypic culture model. Lab. Invest. 70, 916–924 (1994).

    CAS  Google Scholar 

  13. Hertle, M. D., Kubler, M. D., Leigh, I. M. & Watt, F. M. Aberrant integrin expression during epidermal wound healing and in psoriatic epidermis. J. Clin. Invest. 89, 1892–1901 (1992).

    Article  CAS  Google Scholar 

  14. Brieher, W. M. & Gumbiner, B. M. Regulation of C-cadherin function during activin induced morphogenesis of Xenopus animal caps. J. Cell Biol. 126, 519–527 (1994).

    Article  CAS  Google Scholar 

  15. Zhong, Y., Brieher, W. M. & Gumbiner, B. M. Analysis of C-cadherin regulation during tissue morphogenesis with an activating antibody. J. Cell Biol. 144, 351–359 (1999).

    Article  CAS  Google Scholar 

  16. Gumbiner, B. M. Regulation of cadherin adhesive activity. J. Cell Biol. 148, 399–404 (2000).

    Article  CAS  Google Scholar 

  17. Wallis, S. et al. The α isoform of protein kinase C is involved in signaling the response of desmosomes to wounding in cultured epithelial cells. Mol. Biol. Cell 11, 1077–1092 (2000).

    Article  CAS  Google Scholar 

  18. Martin, P. Wound healing—aiming for perfect skin regeneration. Science 276, 75–81 (1997).

    Article  CAS  Google Scholar 

  19. Werner, S. et al. The function of KGF in morphogenesis of epithelium and reepithelialization of wounds. Science 266, 819–822 (1994).

    Article  CAS  Google Scholar 

  20. Guo, L., Degenstein, L. & Fuchs, E. Keratinocyte growth factor is required for hair development but not for wound healing. Genes Dev. 10, 165–175 (1996).

    Article  CAS  Google Scholar 

  21. Hansen, L. A. et al. Genetically null mice reveal a central role for epidermal growth factor receptor in the differentiation of the hair follicle and normal hair development. Am. J. Pathol. 150, 1959–1975 (1997).

    CAS  Google Scholar 

  22. Woolley, K. & Martin, P. Conserved mechanisms of repair: from damaged single cells to wounds in multicellular tissues. BioEssays 22, 911–919 (2000).

    Article  CAS  Google Scholar 

  23. Kolega, J. Effects of mechanical tension on protrusive activity and microfilament and intermediate filament organization in an epidermal epithelium moving in culture. J. Cell Biol. 102, 1400–1411 (1986).

    Article  CAS  Google Scholar 

  24. Verrier, B., Muller, D., Bravo, R. & Muller, R. Wounding a fibroblast monolayer results in the rapid induction of the c-fos proto-oncogene. EMBO J. 5, 913–917 (1986).

    Article  CAS  Google Scholar 

  25. Martin, P. & Nobes, C. D. An early molecular component of the wound healing response in rat embryos—induction of c-fos protein in cells at the epidermal wound margin. Mech. Dev. 38, 209–215 (1992).

    Article  CAS  Google Scholar 

  26. Okada, Y. et al. Expression of fos family and jun family proto-oncogenes during corneal epithelial wound healing. Curr. Eye Res. 15, 824–832 (1996).

    Article  CAS  Google Scholar 

  27. Tran, P. O., Hinman, L. E., Unger, G. M. & Sammak, P. J. A wound-induced [Ca2+]i increase and its transcriptional activation of immediate early genes is important in the regulation of motility. Exp. Cell Res. 246, 319–326 (1999).

    Article  CAS  Google Scholar 

  28. Goliger, J. A. & Paul, D. L. Wounding alters epidermal connexin expression and gap junction-mediated intercellular communication. Mol. Biol. Cell 6, 1491–1501 (1995).

    Article  CAS  Google Scholar 

  29. Martin, P., Dickson, M. C., Millan, F. A. & Akhurst, R. J. Rapid induction and clearance of TGF β1 is an early response to wounding in the mouse embryo. Dev. Genet. 14, 225–238 (1993).

    Article  CAS  Google Scholar 

  30. Ashcroft, G. S. et al. Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nature Cell Biol. 1, 260–266 (1999).

    Article  CAS  Google Scholar 

  31. Matoltsy, A. G. & Viziam, C. B. Further observations on epithelialization of small wounds: an autoradiographic study of incorporation and distribution of 3H-thymidine in the epithelium covering skin wounds. J. Invest. Dermatol. 55, 20–25 (1970).

    Article  CAS  Google Scholar 

  32. Seher, T. C. & Leptin, M. Tribbles, a cell-cycle brake that coordinates proliferation and morphogenesis during Drosophila gastrulation. Curr. Biol. 10, 623–629 (2000).

    Article  CAS  Google Scholar 

  33. Grosshans, J. & Wieschaus, E. A genetic link between morphogenesis and cell division during formation of the ventral furrow in Drosophila. Cell 101, 523–531 (2000).

    Article  CAS  Google Scholar 

  34. Mata, J., Curado, S., Ephrussi, A. & Rorth, P. Tribbles coordinates mitosis and morphogenesis in Drosophila by regulating string/CDC25 proteolysis. Cell 101, 511–522 (2000).

    Article  CAS  Google Scholar 

  35. Martinez-Arias, A. in The Development of Drosophila melanogaster (eds Martinez-Arias, A. & Bate, M.) 517–607 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 1993).

    Google Scholar 

  36. Young, P. E., Richman, A. M., Ketchum, A. S. & Kiehart, D. P. Morphogenesis in Drosophila requires nonmuscle myosin heavy chain function. Genes Dev. 7, 29–41 (1993).

    Article  CAS  Google Scholar 

  37. Harden, N., Loh, H. Y., Chia, W. & Lim, L. A dominant inhibitory version of the small GTP-binding protein Rac disrupts cytoskeletal structures and inhibits developmental cell shape changes in Drosophila. Development 121, 903–914 (1995).

    CAS  Google Scholar 

  38. Harden, N., Ricos, M., Ong, Y. M., Chia, W. & Lim, L. Participation of small GTPases in dorsal closure of the Drosophila embryo: distinct roles for Rho subfamily proteins in epithelial morphogenesis. J. Cell Sci. 112, 273–284 (1999).

    CAS  Google Scholar 

  39. Magie, C. R., Meyer, M. R., Gorsuch, M. S. & Parkhurst, S. M. Mutations in the Rho1 small GTPase disrupt morphogenesis and segmentation during early Drosophila development. Development 126, 5353–5364 (1999).

    CAS  Google Scholar 

  40. Glise, B., Bourbon, H. & Noselli, S. hemipterous encodes a novel Drosophila MAP kinase kinase, required for epithelial cell sheet movement. Cell 83, 451–461 (1995).

    Article  CAS  Google Scholar 

  41. Riesgo-Escovar, J. R., Jenni, M., Fritz, A. & Hafen, E. The Drosophila Jun N-terminal kinase is required for cell morphogenesis but not for DJun-dependent cell fate specification in the eye. Genes Dev. 10, 2759–2768 (1996).

    Article  CAS  Google Scholar 

  42. Riesgo-Escovar, J. R. & Hafen, E. Common and distinct roles of DFos and DJun during Drosophila development. Science 278, 669–672 (1997).

    Article  CAS  Google Scholar 

  43. Glise, B. & Noselli, S. Coupling of Jun amino-terminal kinase and Decapentaplegic signaling pathways in Drosophila morphogenesis. Genes Dev. 11, 1738–1747 (1997).

    Article  CAS  Google Scholar 

  44. Riesgo-Escovar, J. R. & Hafen, E. Drosophila Jun kinase regulates expression of decapentaplegic via the ETS-domain protein Aop and the AP-1 transcription factor DJun during dorsal closure. Genes Dev. 11, 1717–1727 (1997).

    Article  CAS  Google Scholar 

  45. Martin-Blanco, E. et al. puckered encodes a phosphatase that mediates a feedback loop regulating JNK activity during dorsal closure in Drosophila. Genes Dev. 12, 557–570 (1998).

    Article  CAS  Google Scholar 

  46. Zecchini, V., Brennan, K. & Martinez-Arias, A. An activity of Notch regulates JNK signalling and affects dorsal closure in Drosophila. Curr. Biol. 9, 460–469 (1999).

    Article  CAS  Google Scholar 

  47. Abercrombie, M. & Heaysman, J. E. Observations on the social behaviour of cells in tissue culture. Exp. Cell Res. 6, 293–306 (1954).

    Article  CAS  Google Scholar 

  48. Williams-Masson, E. M., Malik, A. N. & Hardin, J. An actin-mediated two-step mechanism is required for ventral enclosure of the C. elegans hypodermis. Development 124, 2889–2901 (1997).

    CAS  Google Scholar 

  49. Raich, W. B., Agbunag, C. & Hardin, J. Rapid epithelial-sheet sealing in the Caenorhabditis elegans embryo requires cadherin-dependent filopodial priming. Curr. Biol. 9, 1139–1146 (1999).

    Article  CAS  Google Scholar 

  50. Adams, C. L., Chen, Y. T., Smith, S. J. & Nelson, W. J. Mechanisms of epithelial cell–cell adhesion and cell compaction revealed by high-resolution tracking of E-cadherin-green fluorescent protein. J. Cell Biol. 142, 1105–1119 (1998).

    Article  CAS  Google Scholar 

  51. Vasioukhin, V., Bauer, C., Yin, M. & Fuchs, E. Directed actin polymerization is the driving force for epithelial cell–cell adhesion. Cell 100, 209–219 (2000).

    Article  CAS  Google Scholar 

  52. Nobes, C. D. & Hall, A. Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell 81, 53–62 (1995).

    Article  CAS  Google Scholar 

  53. Jacinto, A. et al. Dynamic actin-based epithelial adhesion and cell matching during Drosophila dorsal closure. Curr. Biol. 10, 1420–1426 (2000).

    Article  CAS  Google Scholar 

  54. Tessier-Lavigne, M. & Goodman, C. S. The molecular biology of axon guidance. Science 274, 1123–1133 (1996).

    Article  CAS  Google Scholar 

  55. Roy, P. J., Zheng, H., Warren, C. E. & Culotti, J. G. mab-20 encodes Semaphorin-2a and is required to prevent ectopic cell contacts during epidermal morphogenesis in Caenorhabditis elegans. Development 127, 755–767 (2000).

    CAS  Google Scholar 

  56. Morriss-Kay, G. & Tuckett, F. The role of microfilaments in cranial neurulation in rat embryos: effects of short-term exposure to cytochalasin D. J. Embryol. Exp. Morphol. 88, 333–348 (1985).

    CAS  Google Scholar 

  57. Hildebrand, J. D. & Soriano, P. Shroom, a PDZ domain-containing actin-binding protein, is required for neural tube morphogenesis in mice. Cell 99, 485–497 (1999).

    Article  CAS  Google Scholar 

  58. Sabapathy, K. et al. Defective neural tube morphogenesis and altered apoptosis in the absence of both JNK1 and JNK2. Mech. Dev. 89, 115–124 (1999).

    Article  CAS  Google Scholar 

  59. Smeyne, R. J. et al. Continuous c-fos expression precedes programmed cell death in vivo. Nature 363, 166–169 (1993).

    Article  CAS  Google Scholar 

  60. Taya, Y., O'Kane, S. & Ferguson, M. W. Pathogenesis of cleft palate in TGF-β3 knockout mice. Development 126, 3869–3879 (1999).

    CAS  Google Scholar 

  61. Paladini, R. D., Takahashi, K., Bravo, N. S. & Coulombe, P. A. Onset of re-epithelialization after skin injury correlates with a reorganization of keratin filaments in wound edge keratinocytes: defining a potential role for keratin 16. J. Cell Biol. 132, 381–397 (1996).

    Article  CAS  Google Scholar 

  62. Takahashi, K. & Coulombe, P. A. Defining a region of the human keratin 6a gene that confers inducible expression in stratified epithelia of transgenic mice. J. Biol. Chem. 272, 11979–11985 (1997).

    Article  CAS  Google Scholar 

  63. Mazzalupo, S. & Coulombe, P. A. A reporter transgene based on a human keratin 6 gene promoter is specifically expressed in the periderm of mouse embryos. Mech. Dev. 100, 65–69 (2001).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The work in our laboratories is funded by the MRC, Wellcome Trust and Pfizer UK (P.M.) and the Wellcome Trust (A.M.-A.). We thank R. Grose for advice regarding knockout mice studies and we thank W. Wood for all his support.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Paul Martin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jacinto, A., Martinez-Arias, A. & Martin, P. Mechanisms of epithelial fusion and repair. Nat Cell Biol 3, E117–E123 (2001). https://doi.org/10.1038/35074643

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/35074643

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing