title: Loss of Tsc1, but not Pten, in renal tubular cells causes polycystic kidney disease by activating mTORC1.
abstract: Tuberous sclerosis complex (TSC) is a genetic disorder linked to mutations of either the TSC1 or TSC2 gene, which encode proteins that form a complex to negatively regulate mammalian target of rapamycin complex 1 (mTORC1). Clinically, a small percentage of TSC patients develop severe infantile polycystic kidney disease (PKD), which is believed to be caused by deletion of the contiguous TSC2 and PKD1 genes on human chromosome 16. Recent studies have implicated the TSC/mTORC1 signaling pathway in PKD, but how dysfunction of the TSC/mTORC1 pathway induces PKD is not clear. We report a PKD mouse model created by knocking out Tsc1 in a subset of renal tubular cells. Extensive renal cyst formation in these mice is accompanied by broadly elevated mTORC1 activity in both cell autonomous and non-cell autonomous compartments. Furthermore, cyst development requires mTORC1 activation, as low dosage of rapamycin administration effectively blocks cyst formation. Interestingly, disruption of Pten, an upstream regulator of TSC1/TSC2, in the same cells, does not lead to PKD seemingly due to limited activation of mTORC1, suggesting that PTEN may not be a major upstream regulator of TSC/mTORC1 during early postnatal kidney development.
authors.affiliation: Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9133, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.forename: James
authors.initials: J
authors.lastname: Brugarolas
authors.forename: Luis F
authors.initials: LF
authors.lastname: Parada
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D007690:Polycystic Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011506:Proteins; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D011506:Proteins; C000624650:TSC1 protein, human; D014157:Transcription Factors; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase