Profiling of the fetal and adult rat liver transcriptome and translatome reveals discordant regulation by the mechanistic target of rapamycin (mTOR).
The mechanistic target of rapamycin (mTOR) integrates growth factor signaling, nutrient abundance, cell growth, and proliferation. On the basis of our interest in somatic growth in the late gestation fetus, we characterized the role of mTOR in the regulation of hepatic gene expression and translation initiation in fetal and adult rats. Our strategy was to manipulate mTOR signaling in vivo and then characterize the transcriptome and translating mRNA in liver tissue. In adult rats, we used the nonproliferative growth model of refeeding after a period of fasting and the proliferative model of liver regeneration following partial hepatectomy. We also studied livers from preterm fetal rats (embryonic day 19) in which fetal hepatocytes are asynchronously proliferating. All three models employed rapamycin to inhibit mTOR signaling. Analysis of the transcriptome in fasted-refed animals showed rapamycin-mediated induction of genes associated with oxidative phosphorylation. Genes associated with RNA processing were downregulated. In liver regeneration, rapamycin induced genes associated with lysosomal metabolism, steroid metabolism, and the acute phase response. In fetal animals, rapamycin inhibited expression of genes in several functional categories that were unrelated to effects in the adult animals. Translation control showed marked fetal-adult differences. In both adult models, rapamycin inhibited the translation of genes with complex 5' untranslated regions, including those encoding ribosomal proteins. Fetal translation was resistant to the effects of rapamycin. We conclude that the mTOR pathway in liver serves distinct physiological roles in the adult and fetus, with the latter representing a condition of rapamycin resistance.
Division of Pediatric Endocrinology, Rhode Island Hospital and Brown University, Providence, Rhode Island;
Joan M
JM
Boylan
Division of Pediatric Endocrinology, Rhode Island Hospital and Brown University, Providence, Rhode Island; Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island;
Jennifer A
JA
Sanders
Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island.
Nicola
N
Neretti
Division of Pediatric Endocrinology, Rhode Island Hospital and Brown University, Providence, Rhode Island; Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island Philip_Gruppuso@brown.edu.
Philip A
PA
Gruppuso
D000367:Age Factors; D000818:Animals; D049109:Cell Proliferation; D016000:Cluster Analysis; D004351:Drug Resistance; D004435:Eating; D005215:Fasting; D020869:Gene Expression Profiling / Q000379:methods; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005865:Gestational Age; D006498:Hepatectomy; D008099:Liver / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism* / Q000601:surgery; D008115:Liver Regeneration; D020411:Oligonucleotide Array Sequence Analysis; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D059467:Transcriptome / Q000187:drug effects
D012333:RNA, Messenger; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
fetus; liver; protein synthesis; rapamycin; regeneration; translation initiation