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The tyrosine kinase Stitcher activates Grainy head and epidermal wound healing in Drosophila

Nature Cell Biology volume 11, pages 890–895 (2009)Cite this article

Abstract

Epidermal injury initiates a cascade of inflammation, epithelial remodelling and integument repair at wound sites. The regeneration of the extracellular barrier and damaged tissue repair rely on the precise orchestration of epithelial responses triggered by the injury1,2. Grainy head (Grh) transcription factors induce gene expression to crosslink the extracellular barrier in wounded flies and mice3,4. However, the activation mechanisms and functions of Grh factors in re-epithelialization remain unknown. Here we identify stitcher (stit), a new Grh target in Drosophila melanogaster. stit encodes a Ret-family receptor tyrosine kinase required for efficient epidermal wound healing. Live imaging analysis reveals that Stit promotes actin cable assembly during wound re-epithelialization. Stit activation also induces extracellular signal-regulated kinase (ERK) phosphorylation along with the Grh-dependent expression of stit and barrier repair genes at the wound sites. The transcriptional stimulation of stit on injury triggers a positive feedback loop increasing the magnitude of epithelial responses. Thus, Stit activation upon wounding coordinates cytoskeletal rearrangements and the level of Grh-mediated transcriptional wound responses.

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Figure 1: stit is a Grh target gene.
Figure 2: Re-epithelialization defects in stit mutants.
Figure 3: Stit is a tyrosine kinase sufficient for ERK activation in vivo.
Figure 4: Stit localizes apically in epidermal cells and accumulates at wound sites.
Figure 5: Stit activates the induction of wound reporters dependent on ERK and Grh.

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Acknowledgements

We thank W. McGinnis, S. Hayashi, S. Bray, P. Rørth, R. Hodgetts, the Bloomington, the Exelixis–Harvard Stock Centers, Developmental Studies Hybridoma Bank and Drosophila Genomics Resource Center for reagents; H. Jin, J. Hemphälä, M. Björk and I. Granel for technical assistance; and A. Uv, U. Theopold, R. Palmer, K.-A. Senti and colleagues at Wenner-Gren Institute for critical suggestions on the manuscript. Vetenskapsrådet, Cancerfonden and G. Gustafsson Stiftelsen provided financial support.

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  1. Nikos Xylourgidis & Marco Gallio

    Present address: Present addresses: Netherlands Cancer Institute, Department of Tumor Biology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands (N.X.); Neurobiology Section, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0649, USA (M.G.).,

Authors and Affiliations

  1. Department of Developmental Biology, Wenner-Gren Institute, Stockholm University, Stockholm, S-10691, Sweden

    Shenqiu Wang, Vasilios Tsarouhas, Nikos Xylourgidis, Nafiseh Sabri, Katarína Tiklová, Naumi Nautiyal, Marco Gallio & Christos Samakovlis

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Contributions

M.G. and S.W. conducted the bioinformatics analysis. S.W. generated and analysed most strains, helped with live imaging and co-wrote the manuscript. V.T. performed and anlaysed the live imaging and wrote part of the manuscript. N.X. generated and analysed the kinase-dead stit strains and performed quantitative polymerase chain reaction and electrophoretic mobility-shift assays. N.S. conducted immunoprecipitation experiments. K.T. performed the electron microscopy analysis. N.N. generated the stitδ construct. C.S. designed the project, analysed results and co-wrote the manuscript.

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Correspondence to Christos Samakovlis.

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Wang, S., Tsarouhas, V., Xylourgidis, N. et al. The tyrosine kinase Stitcher activates Grainy head and epidermal wound healing in Drosophila. Nat Cell Biol 11, 890–895 (2009). https://doi.org/10.1038/ncb1898

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