Kindlin-1 mutant zebrafish as an in vivo model sytem to study adhesion mechanisms in the epidermis
- Authors
- Postel, R., Margadant, C., Fischer, B., Kreft, M., Janssen, H., Secades, P., Zambruno, G., and Sonnenberg, A.
- ID
- ZDB-PUB-130412-17
- Date
- 2013
- Source
- The Journal of investigative dermatology 133(9): 2180-90 (Journal)
- Registered Authors
- Fischer, Boris, Postel, Ruben
- Keywords
- integrin α3β1, integrin-linked kinase, kindlin-1, Kindler syndrome, zebrafish
- MeSH Terms
-
- Animal Fins/injuries
- Animal Fins/pathology
- Animal Fins/physiology*
- Animals
- Cell Adhesion/physiology*
- Cells, Cultured
- Disease Models, Animal
- Epidermis/cytology*
- Epidermis/physiology
- Epidermolysis Bullosa/genetics
- Epidermolysis Bullosa/pathology
- Epidermolysis Bullosa/physiopathology*
- Fish Diseases/genetics
- Fish Diseases/pathology
- Fish Diseases/physiopathology
- Humans
- Integrin alpha3beta1/genetics
- Integrin alpha3beta1/physiology
- Membrane Proteins/genetics*
- Membrane Proteins/physiology
- Mutation
- Neoplasm Proteins/genetics*
- Neoplasm Proteins/physiology
- Protein Serine-Threonine Kinases/genetics
- Protein Serine-Threonine Kinases/physiology
- Zebrafish/genetics*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/physiology
- PubMed
- 23549420 Full text @ J. Invest. Dermatol.
From a forward genetic screen for epidermal defects in zebrafish, we identified a loss-of-function mutation in Kindlin-1, an essential regulator of integrin function. The mutation generates a premature stop codon, deleting the integrin-binding site. The mutant zebrafish develop cell-matrix and cell-cell adhesion defects in the basal epidermis leading to progressive fin rupturing, and was therefore designated rupturing-of-fins (rof). Similar defects were observed in the epidermis of Kindler syndrome patients, carrying a loss-of-function mutation in kindlin-1. Mutational analysis and rescue experiments in zebrafish revealed that residues K610, W612, and I647 in the F3 domain are essential for Kindlin-1 function in vivo, and that Kindlin-2 can functionally compensate for the loss of Kindlin-1. The fin phenotype of rof/kindlin-1 mutants resembles that of badfin mutants, carrying a mutation in Integrin α3. We show here that this mutation impairs the biosynthesis of integrin α3β1, and causes cell-matrix and cell-cell defects in vivo. Whereas both Integrin-linked kinase and Kindlin-1 cooperate with Integrin α3β1 to resist trauma-induced epidermal defects, Kindlin-1 and Ilk surprisingly do not act synergistically but in parallel. Thus, the rof/kindlin-1 mutant zebrafish provides a unique model system to study epidermal adhesion mechanisms in vivo.