title: TOR deficiency in C. elegans causes developmental arrest and intestinal atrophy by inhibition of mRNA translation.
abstract: BACKGROUND
  TOR is a phosphatidylinositol kinase (PIK)-related kinase that controls cell growth and proliferation in response to nutritional cues. We describe a C. elegans TOR homolog (CeTOR) and phenotypes associated with CeTOR deficiency. These phenotypes are compared with the response to starvation and the inactivation of a variety of putative TOR targets.
  
  
  RESULTS
  Whether caused by mutation or RNA interference, TOR deficiency results in developmental arrest at mid-to-late L3, which is accompanied by marked gonadal degeneration and a pronounced intestinal cell phenotype. A population of refractile, autofluorescent intestinal vesicles, which take up the lysosomal dye Neutral Red, increases dramatically in size, while the number of normal intestinal vesicles and the intestinal cytoplasmic volume decrease progressively. This is accompanied by an increase in the gut lumen size and a compromise in the intestine's ability to digest and absorb nutrients. CeTOR-deficient larvae exhibit no significant dauer characteristics, but share some features with starved L3 larvae. Notably, however, starved larvae do not have severe intestinal atrophy. Inactivation of C. elegans p70S6K or TAP42 homologs does not reproduce CeTOR deficiency phenotypes, nor does inactivation of C. elegans TIP41, a putative negative regulator of CeTOR function, rescue CeTOR deficiency. In contrast, inactivating the C. elegans eIF-4G homolog and eIF-2 subunits results in developmental arrest accompanied by the appearance of large, refractile intestinal vesicles and severe intestinal atrophy resembling that of CeTOR deficiency.
  
  
  CONCLUSIONS
  The developmental arrest and intestinal phenotypes of CeTOR deficiency are due to an inhibition of global mRNA translation. Thus, TOR is a major upstream regulator of overall mRNA translation in C. elegans, as in yeast.
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: Long
authors.forename: Carmen
authors.initials: C
authors.lastname: Spycher
authors.forename: Z Stanley
authors.initials: ZS
authors.lastname: Han
authors.forename: Ann M
authors.initials: AM
authors.lastname: Rose
authors.forename: Fritz
authors.initials: F
authors.lastname: Müller
authors.forename: Joseph
authors.initials: J
authors.lastname: Avruch
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics; D000483:Alleles; D000818:Animals; D001284:Atrophy; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000302:isolation & purification / Q000494:pharmacology* / Q000502:physiology*; D015852:Eukaryotic Initiation Factor-2 / Q000172:deficiency / Q000502:physiology; D039603:Eukaryotic Initiation Factor-4G / Q000172:deficiency / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D005804:Genes, Lethal; D005816:Genetic Complementation Test; D007422:Intestines / Q000254:growth & development / Q000473:pathology; D007814:Larva; D010641:Phenotype; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000302:isolation & purification / Q000494:pharmacology*; D014176:Protein Biosynthesis; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D020123:Sirolimus / Q000494:pharmacology; D013045:Species Specificity; D013217:Starvation
chemical_list: D029742:Caenorhabditis elegans Proteins; D015852:Eukaryotic Initiation Factor-2; D039603:Eukaryotic Initiation Factor-4G; D012333:RNA, Messenger; D017853:Phosphotransferases (Alcohol Group Acceptor); C472494:let-363 protein, C elegans; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020123:Sirolimus