Smooth muscle tension induces invasive remodeling of the zebrafish intestine

PLoS Biol. 2012;10(9):e1001386. doi: 10.1371/journal.pbio.1001386. Epub 2012 Sep 4.


The signals that initiate cell invasion are not well understood, but there is increasing evidence that extracellular physical signals play an important role. Here we show that epithelial cell invasion in the intestine of zebrafish meltdown (mlt) mutants arises in response to unregulated contractile tone in the surrounding smooth muscle cell layer. Physical signaling in mlt drives formation of membrane protrusions within the epithelium that resemble invadopodia, matrix-degrading protrusions present in invasive cancer cells. Knockdown of Tks5, a Src substrate that is required for invadopodia formation in mammalian cells blocked formation of the protrusions and rescued invasion in mlt. Activation of Src-signaling induced invadopodia-like protrusions in wild type epithelial cells, however the cells did not migrate into the tissue stroma, thus indicating that the protrusions were required but not sufficient for invasion in this in vivo model. Transcriptional profiling experiments showed that genes responsive to reactive oxygen species (ROS) were upregulated in mlt larvae. ROS generators induced invadopodia-like protrusions and invasion in heterozygous mlt larvae but had no effect in wild type larvae. Co-activation of oncogenic Ras and Wnt signaling enhanced the responsiveness of mlt heterozygotes to the ROS generators. These findings present the first direct evidence that invadopodia play a role in tissue cell invasion in vivo. In addition, they identify an inducible physical signaling pathway sensitive to redox and oncogenic signaling that can drive this process.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actins / metabolism
  • Animals
  • Basement Membrane / metabolism
  • Cell Movement*
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Extracellular Matrix / metabolism
  • Heterozygote
  • Homozygote
  • Intestines / pathology*
  • Intestines / physiopathology*
  • Larva / metabolism
  • Mechanotransduction, Cellular
  • Muscle Contraction / physiology
  • Muscle Tonus / physiology*
  • Muscle, Smooth / physiology*
  • Mutation / genetics
  • Oncogenes / genetics
  • Oxidation-Reduction
  • Oxidative Stress
  • Pseudopodia / metabolism
  • Signal Transduction
  • Zebrafish / physiology*
  • Zebrafish Proteins / metabolism
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / metabolism


  • Actins
  • Zebrafish Proteins
  • src-Family Kinases