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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 arhgef25b, 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.
Highlights
Skin conditions generate between 12% to 43% of medical visits [1, 2]
We identified neuregulin 2a as a novel essential regulator of apical median fin fold (MFF) development and MFF ridge cell polarity. nrg2a is a zebrafish homolog of the epidermal growth factor (EGF) superfamily member NEUREGULIN 2 (NRG2)
Locating expression within a tissue of interest is a key step toward identifying new genes involved in tissue-specific biology
Summary
Skin conditions generate between 12% to 43% of medical visits [1, 2]. In the United States, skin disorders are estimated to affect one third of the population at any time, with an estimated total annual cost of nearly US$100 billion [3]. Patients with skin disease frequently suffer physical discomfort and pain, and often experience diminished quality of life and psychological distress [4,5,6]. Skin conditions are challenging to treat: skin is an exposed, physically vulnerable external barrier whose continuous turnover can impede long-lasting healing. Because there is a limited variety of clinical treatment methods, many of which are non-specific immune modulators such as steroids [7], new therapeutic targets for skin conditions could have important health and economic benefits [8]. Strategies for identifying novel integument genes and expanding our understanding of incompletely characterized integument loci offer avenues for subsequent interventional approaches
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