PUBLICATION

Smooth muscle tension induces invasive remodeling of the zebrafish intestine

Authors
Seiler, C., Davuluri, G., Abrams, J., Byfield, F.J., Janmey, P.A., and Pack, M.
ID
ZDB-PUB-120927-26
Date
2012
Source
PLoS Biology   10(9): e1001386 (Journal)
Registered Authors
Abrams, Joshua, Pack, Michael, Seiler, Christoph
Keywords
Larvae, Gastrointestinal tract, Smooth muscles, Epithelial cells, Muscle contraction, Epithelium, Redox signaling, Zebrafish
MeSH Terms
  • Epithelial Cells/metabolism
  • Epithelial Cells/pathology
  • Oxidative Stress
  • Pseudopodia/metabolism
  • Intestines/pathology*
  • Intestines/physiopathology*
  • Muscle Tonus/physiology*
  • Larva/metabolism
  • Oxidation-Reduction
  • Signal Transduction
  • Zebrafish Proteins/metabolism
  • Oncogenes/genetics
  • Mechanotransduction, Cellular
  • Animals
  • Homozygote
  • Basement Membrane/metabolism
  • Muscle Contraction/physiology
  • Heterozygote
  • Extracellular Matrix/metabolism
  • Mutation/genetics
  • Muscle, Smooth/physiology*
  • Zebrafish/physiology*
  • src-Family Kinases/antagonists & inhibitors
  • src-Family Kinases/metabolism
  • Cell Movement*
  • Actins/metabolism
(all 26)
PubMed
22973180 Full text @ PLoS Biol.
Abstract

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.

Genes / Markers
Figures
Figure Gallery (17 images) / 2
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
m498
    Point Mutation
    p151TgTransgenic Insertion
      p306TgTransgenic Insertion
        p307TgTransgenic Insertion
          p308TgTransgenic Insertion
            p309TgTransgenic Insertion
              p310TgTransgenic Insertion
                p311TgTransgenic Insertion
                  p312TgTransgenic Insertion
                    p313TgTransgenic Insertion
                      1 - 10 of 11
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                      Human Disease / Model
                      No data available
                      Sequence Targeting Reagents
                      Target Reagent Reagent Type
                      acta2MO1-acta2MRPHLNO
                      cald1aMO1-cald1aMRPHLNO
                      sh3pxd2aaMO1-sh3pxd2aaMRPHLNO
                      1 - 3 of 3
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                      Fish
                      Antibodies
                      Orthology
                      No data available
                      Engineered Foreign Genes
                      Marker Marker Type Name
                      GFPEFGGFP
                      mCherryEFGmCherry
                      roGFPEFGroGFP
                      1 - 3 of 3
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                      Mapping
                      No data available