Universität zu Köln

Westcot, Stephanie E., Hatzold, Julia ORCID: 0000-0002-5491-1921, Urban, Mark D., Richetti, Stefania K., Skuster, Kimberly J., Harm, Rhianna M., Cervera, Roberto Lopez, Umemoto, Noriko, McNulty, Melissa S., Clark, Karl J., Hammerschmidt, Matthias and Ekker, Stephen C. (2015). Protein-Trap Insertional Mutagenesis Uncovers New Genes Involved in Zebrafish Skin Development, Including a Neuregulin 2a-Based ErbB Signaling Pathway Required during Median Fin Fold Morphogenesis. PLoS One, 10 (6). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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Abstract

Skin disorders are widespread, but available treatments are limited. A more comprehensive understanding of skin development mechanisms will drive identification of new treatment targets and modalities. Here we report the Zebrafish Integument Project (ZIP), an expression-driven platform for identifying new skin genes and phenotypes in the vertebrate model Danio rerio (zebrafish). In vivo selection for skin-specific expression of gene-break transposon (GBT) mutant lines identified eleven new, revertible GBT alleles of genes involved in skin development. Eight genes-fras1, grip1, hmcn1, msxc, col4a4, ahnak, capn12, and nrg2a-had been described in an integumentary context to varying degrees, while arh-gef25b, fkbp10b, and megf6a emerged as novel skin genes. Embryos homozygous for a GBT insertion within neuregulin 2a (nrg2a) revealed a novel requirement for a Neuregulin 2a (Nrg2a) - ErbB2/3 - AKT signaling pathway governing the apicobasal organization of a subset of epidermal cells during median fin fold (MFF) morphogenesis. In nrg2a mutant larvae, the basal keratinocytes within the apical MFF, known as ridge cells, displayed reduced pAKT levels as well as reduced apical domains and exaggerated basolateral domains. Those defects compromised proper ridge cell elongation into a flattened epithelial morphology, resulting in thickened MFF edges. Pharmacological inhibition verified that Nrg2a signals through the ErbB receptor tyrosine kinase network. Moreover, knockdown of the epithelial polarity regulator and tumor suppressor lgl2 ameliorated the nrg2a mutant phenotype. Identifying Lgl2 as an antagonist of Nrg2a - ErbB signaling revealed a significantly earlier role for Lgl2 during epidermal morphogenesis than has been described to date. Furthermore, our findings demonstrated that successive, coordinated ridge cell shape changes drive apical MFF development, making MFF ridge cells a valuable model for investigating how the coordinated regulation of cell polarity and cell shape changes serves as a crucial mechanism of epithelial morphogenesis.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Westcot, Stephanie E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hatzold, Julia UNSPECIFIED orcid.org/0000-0002-5491-1921 UNSPECIFIED Urban, Mark D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Richetti, Stefania K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Skuster, Kimberly J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Harm, Rhianna M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cervera, Roberto Lopez UNSPECIFIED UNSPECIFIED UNSPECIFIED Umemoto, Noriko UNSPECIFIED UNSPECIFIED UNSPECIFIED McNulty, Melissa S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Clark, Karl J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hammerschmidt, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Ekker, Stephen C. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-400895
DOI:	10.1371/journal.pone.0130688
Journal or Publication Title:	PLoS One
Volume:	10
Number:	6
Date:	2015
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1932-6203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language LETHAL-GIANT-LARVAE; QUALITY-OF-LIFE; FRASER-SYNDROME; CELL-MIGRATION; EXTRACELLULAR-MATRIX; TRANSGENIC ZEBRAFISH; NUCLEAR-LOCALIZATION; BLEBBED PHENOTYPE; GROWTH-FACTOR; NEURAL CREST Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/40089