A Drosophila Model of Epidermolysis Bullosa Simplex

Autor(en): Bohnekamp, Jens
Cryderman, Diane E.
Paululat, Achim 
Baccam, Gabriel C.
Wallrath, Lori L.
Magin, Thomas M.
Stichwörter: CELLS; CYTOKERATINS; Dermatology; GENE-EXPRESSION; GENERATION; KERATIN INTERMEDIATE-FILAMENTS; MICE; NETWORK; ORGANIZATION; SKIN; TRANSFORMATION
Erscheinungsdatum: 2015
Herausgeber: ELSEVIER SCIENCE INC
Journal: JOURNAL OF INVESTIGATIVE DERMATOLOGY
Volumen: 135
Ausgabe: 8
Startseite: 2031
Seitenende: 2039
Zusammenfassung: 
The blistering skin disorder epidermolysis bullosa simplex (EBS) results from dominant mutations in keratin 5 (K5) or keratin 14 (K14) genes, encoding the intermediate filament (IF) network of basal epidermal keratinocytes. The mechanisms governing keratin network formation and collapse due to EBS mutations remain incompletely understood. Drosophila lacks cytoplasmic IFs, providing a `null' environment to examine the formation of keratin networks and determine mechanisms by which mutant keratins cause pathology. Here, we report that ubiquitous co-expression of transgenes encoding wild-type human K14 and K5 resulted in the formation of extensive keratin networks in Drosophila epithelial and non-epithelial tissues, causing no overt phenotype. Similar to mammalian cells, treatment of transgenic fly tissues with phosphatase inhibitors caused keratin network collapse, validating Drosophila as a genetic model system to investigate keratin dynamics. Co-expression of K5 and a K14(R125C) mutant that causes the most severe form of EBS resulted in widespread formation of EBS-like cytoplasmic keratin aggregates in epithelial and non-epithelial fly tissues. Expression of K14(R125C)/K5 caused semi-lethality; adult survivors developed wing blisters and were flightless due to a lack of intercellular adhesion during wing heart development. This Drosophila model of EBS is valuable for the identification of pathways altered by mutant keratins and for the development of EBS therapies.
ISSN: 0022202X
DOI: 10.1038/jid.2015.129

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