TOR deficiency in C. elegans causes developmental arrest and intestinal atrophy by inhibition of mRNA translation.
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.
Long
Xiaomeng
X
Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
Spycher
Carmen
C
Han
Z Stanley
ZS
Rose
Ann M
AM
Müller
Fritz
F
Avruch
Joseph
J
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
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