Mutation of smooth muscle myosin causes epithelial invasion and cystic expansion of the zebrafish intestine.
Zebrafish meltdown (mlt) mutants develop cystic expansion of the posterior intestine as a result of stromal invasion of nontransformed epithelial cells. Positional cloning identified zebrafish smooth muscle myosin heavy chain (myh11) as the responsible gene. The mlt mutation constitutively activates the Myh11 ATPase, which disrupts smooth muscle cells surrounding the posterior intestine. Adjacent epithelial cells ectopically express metalloproteinases, integrins, and other genes implicated in human cancer cell invasion. Knockdown and pharmacological inhibition of these genes restores intestinal structure in mlt mutants despite persistent smooth muscle defects. These data identify an essential role for smooth muscle signaling in the maintenance of epithelial architecture and support gene expression analyses and other studies that identify a role for stromal genes in cancer cell invasion. Furthermore, they suggest that high-throughput screens to identify regulators of cancer cell invasion may be feasible in zebrafish.
Wallace
Kenneth N
KN
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, 19104, USA.
Dolan
Amy C
AC
Seiler
Christoph
C
Smith
Erin M
EM
Yusuff
Shamila
S
Chaille-Arnold
Linda
L
Judson
Ben
B
Sierk
Rachel
R
Yengo
Christopher
C
Sweeney
H Lee
HL
Pack
Michael
M
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D004848:Epithelium / Q000254:growth & development; D006801:Humans; D017403:In Situ Hybridization; D007422:Intestines / Q000254:growth & development*; D008969:Molecular Sequence Data; D009130:Muscle, Smooth / Q000254:growth & development / Q000378:metabolism; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism*
D029961:Zebrafish Proteins; D004247:DNA; D018995:Myosin Heavy Chains