Inactivation of serine protease Matriptase1a by its inhibitor Hai1 is required for epithelial integrity of the zebrafish epidermis

Thomas J. Carney, Sophia von der Hardt, Carmen Sonntag, Adam Amsterdam, Jacek Topczewski, Nancy Hopkins, Matthias Hammerschmidt*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

Abstract

Epithelial integrity requires the adhesion of cells to each other as well as to an underlying basement membrane. The modulation of adherence properties is crucial to morphogenesis and wound healing, and deregulated adhesion has been implicated in skin diseases and cancer metastasis. Here, we describe zebrafish that are mutant in the serine protease inhibitor Hai 1a (Spint 1la), which display disrupted epidermal integrity. These defects are further enhanced upon combined loss of hai 1a and its paralog hai 1b. By applying in vivo imaging, we demonstrate that Hai1-deficient keratinocytes acquire mesenchymal-like characteristics, lose contact with each other, and become mobile and more susceptible to apoptosis. In addition, inflammation of the mutant skin is evident, although not causative of the epidermal defects. Only later, the epidermis exhibits enhanced cell proliferation. The defects of hai1 mutants can be phenocopied by overexpression and can be fully rescued by simultaneous inactivation of the serine protease Matriptase 1a (St14a), indicating that Hai1 promotes epithelial integrity by inhibiting Matriptase1a. By contrast, Hepatocyte growth factor (Hgf), a well-known promoter of epithelial-mesenchymal transitions and a prime target of Matriptasel activity, plays no major role. Our work provides direct genetic evidence for antagonistic in vivo roles of Hai1 and Matriptase1a to regulate skin homeostasis and remodeling.

Original languageEnglish (US)
Pages (from-to)3461-3471
Number of pages11
JournalDevelopment
Volume134
Issue number19
DOIs
StatePublished - Oct 2007

Keywords

  • EMT
  • Epidermis
  • HGF
  • Hai1
  • Matriptase1
  • Met
  • Scattering
  • Spint1
  • St14
  • Zebrafish

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

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