Kindlin-1 Mutant Zebrafish as an In Vivo Model System to Study Adhesion Mechanisms in the Epidermis Ruben Postel, Coert Margadant, Boris Fischer, Maaike.

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Kindlin-1 Mutant Zebrafish as an In Vivo Model System to Study Adhesion Mechanisms in the Epidermis Ruben Postel, Coert Margadant, Boris Fischer, Maaike Kreft, Hans Janssen, Pablo Secades, Giovanna Zambruno, Arnoud Sonnenberg Journal of Investigative Dermatology Volume 133, Issue 9, Pages 2180-2190 (September 2013) DOI: 10.1038/jid.2013.154 Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Mutation in kindlin-1 causes progressive rupturing-of-fins (rof) in zebrafish. (a) Medial fins of wild-type and rof mutant zebrafish. d.p.f., days post fertilization. (b) Quantification of medial fin outgrowth. (c) Linkage analysis of the rof locus. Arrows indicate direction of the mutation; red line indicates open reading frame of the transcript. Chr. 20, chromosome 20. (d) In situ hybridization for kindlin-1 in wild-type embryos. Inset shows gut epithelium. h.p.f., hours post fertilization. (e) Medial fins of noninjected control (nic) and wild-type embryos injected with a kindlin-1 ATG morpholino (ATG-MO) or splice-site morpholino (splice-MO). (f) Sequence of wild-type and rof/kindlin-1 mutant complementary DNA (cDNA). Arrow indicates the mutation. (g) mRNA expression of kindlin-1 (ef1α=cDNA input control) in wild-type (wt) and rof/kindlin-1 embryos. (h) Structure of wild-type and mutant zebrafish (zf) Kindlin-1. (i) Medial fins of rof/kindlin-1 embryos injected with zfKindlin-1, zfKindlin-1del565, human (hu)kindlin-1, or hukindlin-1KWI>AAA. Journal of Investigative Dermatology 2013 133, 2180-2190DOI: (10.1038/jid.2013.154) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Cell–matrix and cell–cell contact defects in rof/kindlin-1 mutants. (a) Electron microscopy of wild-type (left) and rof/kindlin-1 mutant (right) embryos at 2 days post fertilization (d.p.f.). Black arrows mark the sites of cell–cell contact, arrowheads mark the basement membrane, and asterisks mark cell–matrix and cell–cell contact defects. a, actinotrichia; be, basal epidermis; e, epidermis; ecm, extracellular matrix; pe, periderm. Bars=5μm (top) and 1μm (bottom). (b) Whole-mount immunostaining of E-cadherin in wild-type (left) and rof/kindlin-1 (right) mutant embryos at 6 d.p.f. Boxed region is enlarged in the inset. Arrows point toward punctate cytoplasmic E-cadherin compartments. Bars=40μm (left) and 10μm (right). (c) Labeling of F-actin (green) and p63 (red) in basal epidermis and periderm of wild-type and rof/kindlin-1 mutant embryos at 6 d.p.f. Bar=10μm. Journal of Investigative Dermatology 2013 133, 2180-2190DOI: (10.1038/jid.2013.154) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Loss-of-function mutations in kindlin-1 cause cell–matrix and cell–cell contact defects in the epidermis in Kindler syndrome (KS) patients. Immunostaining of E-cadherin (red) and laminin-332 (Ln-332; green) in the skin of two KS patients and an unaffected individual (normal). Nuclei were counterstained with 4',6-diamidino-2-phenylindole (DAPI). Arrows indicate basement membrane (BM) abnormalities and arrowheads mark defects in cell–cell contacts. Bar=50μm. d, dermis; e, epidermis. Journal of Investigative Dermatology 2013 133, 2180-2190DOI: (10.1038/jid.2013.154) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Disruption of α3β1 biosynthesis causes cell–matrix and cell–cell contact defects. (a) The S427 residue in α3, mutated in bdf/itga3, and its human homolog S433. aa, amino acid. (b) Arrow indicates position of S433 in the β-propeller of α3. (c) Box shows position of S433 in the FG-GAP repeats. (d) Expression of precursor and mature α3 in MKα3−, MKα3wt, and MKα3S433P keratinocytes. (e) Cell-surface expression of α3 in MKα3−, MKα3wt, and MKα3S433P. (f) Adhesion to laminin-511 (Ln-511) and collagen-1 (Col-1). White bars, GoH3. Values shown are averages ±SD from three independent experiments (**p<0.005). (g) Cell spreading over Ln-511 and Col-1. White bars, GoH3. Values shown are averages ±SD from three independent experiments (*p<0.05, **p<0.005, ***p<0.001). (h) Electron microscopy of bdf/itga3 embryo (2 days post fertilization (d.p.f.)). Arrows indicate cell–cell contact defects and asterisks indicate cell–matrix defects. be, basal epidermis; ecm, extracellular matrix; pe, periderm. Bar=2μm. (i) E-cadherin and β-catenin in wild-type and bdf/itga3 epidermis (6 d.p.f.). Bar=10μm. Journal of Investigative Dermatology 2013 133, 2180-2190DOI: (10.1038/jid.2013.154) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Kindlin-2 expression rescues the trauma-induced fin rupturing in rof/kindlin-1 mutants. (a) Medial fins of wild-type and rof/kindlin-1 embryos at 3 days post fertilization (d.p.f.) and 6 d.p.f. cultured in viscous medium (VM) supplemented with a low dose of anesthetics (LA). (b) Quantification of the outgrowth of the medial fins. Shown are the means±SD (*p<0.05, **p<0.01). (c) Rescue of medial fin rupturing at 3 d.p.f. in rof/kindlin-1 embryos by ectopic expression of zebrafish (zf) Kindlin-2 or human (hu) kindlin-2. (d) Green fluorescent protein (GFP)–tagged zf-Kindlin-1 and mouse kindlin-2 were expressed in rof/kindlin-1 embryos, and distribution of the kindlins (green) in the basal epidermis and the periderm was investigated at 3 d.p.f. in whole mounts of the medial fin. Basal epidermal cells were identified by p63 staining. Bars=100μm. Journal of Investigative Dermatology 2013 133, 2180-2190DOI: (10.1038/jid.2013.154) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Integrin-linked kinase (Ilk) and Kindlin-1 do not act synergistically in the basal epidermis of zebrafish. (a–d) Morphology of the medial fins of homozygous (a) wild-type, (b) loc/ilk, (c) rof/kindlin-1, and (d) loc/ilk // rof/kindlin-1 embryos at 3 days post fertilization (d.p.f.). (e–i) Morphology of the medial fins of wild-type embryos at 3 d.p.f. after injection of suboptimal doses of morpholinos (MOs) against (e) kindlin-1, (f) itga3, (g) ilk, (h) itga3 and kindlin-1, or (i) itga3 and ilk. (j–l) Morphology of the medial fins of wild-type embryos at 3 d.p.f. after coinjection of (j) MOs against itga3 and kindlin-1 together with kindlin-1 RNA, (k) MOs against itga3 and ilk together with ilk RNA, or (l) MOs against kindlin-1 and ilk. Journal of Investigative Dermatology 2013 133, 2180-2190DOI: (10.1038/jid.2013.154) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions