Vivo-Morpholinos: Same oligos, from cultures to critters -


Elevated expression of the V-ATPase C subunit triggers JNK-dependent cell invasion and overgrowth in a Drosophila epithelium
Astrid G. Petzoldt, Eva Maria Gleixner, Arianna Fumagalli, Thomas Vaccari, Matias Simons


The C subunit of the vacuolar H+-ATPase or V-ATPase regulates the activity and assembly of the proton pump at cellular membranes. It has been shown to be strongly upregulated in oral squamous cell carcinoma, a highly metastatic epithelial cancer. In addition, increased V-ATPase activity appears to correlate with invasiveness of cancer cells, but the underlying mechanism is largely unknown. Using the Drosophila wing imaginal epithelium as an in vivo model system, we demonstrate that overexpression of Vha44, the Drosophila orthologue of the C subunit, causes a tumor-like tissue transformation in cells of the wing epithelium. Overexpressing cells are excluded from the epithelium and acquire invasive properties while displaying high apoptotic rates. Blocking apoptosis in these cells unmasks a strong proliferation stimulus, leading to overgrowth. Furthermore, we show that excess Vha44 greatly increases acidification of endocytic compartments and interferes with endosomal trafficking. As a result, cargoes such as GFP-Lamp1 and Notch accumulate in highly acidified enlarged endolysosomal compartments. Consistent with previous reports on the endocytic activation of Eiger/JNK signaling, we find that V-ATPase stimulation by Vha44 causes JNK signaling activation whereas downmodulation of JNK signaling rescues the invasive phenotypes. In summary, our in vivo-findings demonstrate that increased levels of V-ATPase C subunit induce a Eiger/JNK-dependent cell transformation within an epithelial organ that recapitulates early carcinoma stages.



    The authors declare that they do not have any competing or financial interests.


    A.G.P. and M.S. conceived the project based on the initial observation of the Vha44 phenotype. A.G.P., E.M.G. and A.F. designed and performed the experiments and analyzed the data. T.V. and M.S. designed the experiments and analyzed the data. T.V. and M.S. wrote the manuscript. All authors read, discussed and edited the manuscript.


    A.G.P., E.M.G. and M.S. are supported by an Emmy-Noether grant [grant number SI1303/2-1] by the Deutsche Forschungsgemeinschaft and by the Bundesministerium für Bildung und Forschung (Gerontosys-NephAge). A.F. and T.V. are supported by a new unit start-up grant from Associazione Italiana Ricerca contro il Cancro.


    Supplementary material for this article is available at

  • Received August 1, 2012.
  • Accepted January 14, 2013.

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