GRHL3 activates FSCN1 to relax cell-cell adhesions between migrating keratinocytes during wound reepithelialization

JCI Insight. 2021 Sep 8;6(17):e142577. doi: 10.1172/jci.insight.142577.


The migrating keratinocyte wound front is required for skin wound closure. Despite significant advances in wound healing research, we do not fully understand the molecular mechanisms that orchestrate collective keratinocyte migration. Here, we show that, in the wound front, the epidermal transcription factor Grainyhead like-3 (GRHL3) mediates decreased expression of the adherens junction protein E-cadherin; this results in relaxed adhesions between suprabasal keratinocytes, thus promoting collective cell migration and wound closure. Wound fronts from mice lacking GRHL3 in epithelial cells (Grhl3-cKO) have lower expression of Fascin-1 (FSCN1), a known negative regulator of E-cadherin. Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) on wounded keratinocytes shows decreased wound-induced chromatin accessibility near the Fscn1 gene in Grhl3-cKO mice, a region enriched for GRHL3 motifs. These data reveal a wound-induced GRHL3/FSCN1/E-cadherin pathway that regulates keratinocyte-keratinocyte adhesion during wound-front migration; this pathway is activated in acute human wounds and is altered in diabetic wounds in mice, suggesting translational relevance.

Keywords: Cell migration/adhesion; Dermatology; Genetics; Skin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / biosynthesis
  • Carrier Proteins / genetics*
  • Cell Adhesion / genetics*
  • Cell Line
  • Cell Movement / genetics
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / genetics*
  • Disease Models, Animal
  • Epidermis / injuries*
  • Epidermis / metabolism
  • Epidermis / pathology
  • Gene Expression Regulation*
  • Keratinocytes / metabolism
  • Mice
  • Microfilament Proteins / biosynthesis
  • Microfilament Proteins / genetics*
  • RNA / genetics*
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics*
  • Wound Healing*


  • Carrier Proteins
  • DNA-Binding Proteins
  • FSCN1 protein, human
  • Grhl3 protein, mouse
  • Microfilament Proteins
  • Transcription Factors
  • RNA