title: Target of rapamycin (TOR) signaling controls epithelial morphogenesis in the vertebrate intestine.
abstract: The target of rapamycin (TOR) signaling pathway regulates cell growth and proliferation, however the extent to which TOR signaling mediates particular organogenesis programs remains to be determined. Here we report an examination of TOR signaling during zebrafish development, using a combination of small molecule treatment and morpholino-mediated gene knockdown. First, we amplified and sequenced the full-length cDNA for the zebrafish TOR ortholog (ztor). By in situ hybridization, we found that ztor is expressed ubiquitously in the early embryo, but displays a dynamic pattern in the gut between 48 and 72 h post-fertilization (hpf). Treatment of zebrafish embryos with rapamycin induced only a mild general developmental delay up to 72 hpf, but digestive tract development became arrested at the primitive gut tube stage. Rapamycin inhibited intestinal epithelial growth, morphogenesis and differentiation. Using morpholino-mediated gene knockdown of TOR pathway components, we show that this effect is mediated specifically by the rapamycin-sensitive TOR complex 1 (TORC1). Thus, in addition to regulating cell growth and proliferation, TOR signaling controls the developmental program guiding epithelial morphogenesis in the vertebrate intestine.
authors.affiliation: Gastroenterology Section, Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Khadijah
authors.initials: K
authors.lastname: Makky
authors.forename: Jackie
authors.initials: J
authors.lastname: Tekiela
authors.forename: Alan N
authors.initials: AN
authors.lastname: Mayer
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D047108:Embryonic Development / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D004848:Epithelium / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects / Q000196:embryology*; D009024:Morphogenesis; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D029961:Zebrafish Proteins; D011494:Protein Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus