title: Mutation of smooth muscle myosin causes epithelial invasion and cystic expansion of the zebrafish intestine.
abstract: 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.
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, 19104, USA.
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Wallace
authors.forename: Amy C
authors.initials: AC
authors.lastname: Dolan
authors.forename: Christoph
authors.initials: C
authors.lastname: Seiler
authors.forename: Erin M
authors.initials: EM
authors.lastname: Smith
authors.forename: Shamila
authors.initials: S
authors.lastname: Yusuff
authors.forename: Linda
authors.initials: L
authors.lastname: Chaille-Arnold
authors.forename: Ben
authors.initials: B
authors.lastname: Judson
authors.forename: Rachel
authors.initials: R
authors.lastname: Sierk
authors.forename: Christopher
authors.initials: C
authors.lastname: Yengo
authors.forename: H Lee
authors.initials: HL
authors.lastname: Sweeney
authors.forename: Michael
authors.initials: M
authors.lastname: Pack
mesh_terms: 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*
chemical_list: D029961:Zebrafish Proteins; D004247:DNA; D018995:Myosin Heavy Chains