title: Kindlin-1 mutant zebrafish as an in vivo model system to study adhesion mechanisms in the epidermis.
abstract: 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 develops 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 (Ilk) 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.
authors.affiliation: The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Ruben
authors.initials: R
authors.lastname: Postel
authors.forename: Coert
authors.initials: C
authors.lastname: Margadant
authors.forename: Boris
authors.initials: B
authors.lastname: Fischer
authors.forename: Maaike
authors.initials: M
authors.lastname: Kreft
authors.forename: Hans
authors.initials: H
authors.lastname: Janssen
authors.forename: Pablo
authors.initials: P
authors.lastname: Secades
authors.forename: Giovanna
authors.initials: G
authors.lastname: Zambruno
authors.forename: Arnoud
authors.initials: A
authors.lastname: Sonnenberg
mesh_terms: D058500:Animal Fins / Q000293:injuries / Q000473:pathology / Q000502:physiology*; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000078404:Epidermal Cells; D004817:Epidermis / Q000502:physiology; D004820:Epidermolysis Bullosa / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D005393:Fish Diseases / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D039201:Integrin alpha3beta1 / Q000235:genetics / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology; D015027:Zebrafish / Q000235:genetics*; D029961:Zebrafish Proteins / Q000235:genetics / Q000502:physiology; D000099200:Scaffold Protein ILK
chemical_list: D039201:Integrin alpha3beta1; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D017346:Protein Serine-Threonine Kinases; D029961:Zebrafish Proteins; C475301:FERMT1 protein, human; C477322:FERMT3 protein, human; C584064:fermt1 protein, zebrafish; C522180:ILK protein, zebrafish; D000099200:Scaffold Protein ILK