Inactivation of serine protease Matriptase1a by its inhibitor Hai1 is required for epithelial integrity of the zebrafish epidermis.
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 Hai1a (Spint1la), which display disrupted epidermal integrity. These defects are further enhanced upon combined loss of hai1a and its paralog hai1b. 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 Matriptase1a (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 Matriptase1 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.
Carney
Thomas J
TJ
Max-Planck-Institute of Immunobiology, Stuebeweg 51, D-79108 Freiburg, Germany.
von der Hardt
Sophia
S
Sonntag
Carmen
C
Amsterdam
Adam
A
Topczewski
Jacek
J
Hopkins
Nancy
N
Hammerschmidt
Matthias
M
D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D004817:Epidermis / Q000196:embryology / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D016254:Mutagenesis, Insertional; D010641:Phenotype; D053491:Proteinase Inhibitory Proteins, Secretory / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D053491:Proteinase Inhibitory Proteins, Secretory; D015842:Serine Proteinase Inhibitors; D029961:Zebrafish Proteins; D012697:Serine Endopeptidases; C485595:matriptase