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Nat Commun. 2016 Mar 2;7:10786. doi: 10.1038/ncomms10786.

mTORC1-mediated inhibition of polycystin-1 expression drives renal cyst formation in tuberous sclerosis complex.

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Division of Genetics and Cell Biology, Dibit San Raffaele Scientific Institute, Via Olgettina, 58, Milano 20132, Italy.
PhD Program in Biology and Biotherapy of Cancer, Università Vita-Salute San Raffaele, Via Olgettina, 58, Milano 20132, Italy.
Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
INGM, Via Sforza 28, Milano 20122, Italy.
Department of Internal Medicine and Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520-8029, USA.
Department of Biosciences, University of Milan, Via Celoria, 26, Milano 20133, Italy.


Previous studies report a cross-talk between the polycystic kidney disease (PKD) and tuberous sclerosis complex (TSC) genes. mTOR signalling is upregulated in PKD and rapamycin slows cyst expansion, whereas renal inactivation of the Tsc genes causes cysts. Here we identify a new interplay between the PKD and TSC genes, with important implications for the pathophysiology of both diseases. Kidney-specific inactivation of either Pkd1 or Tsc1 using an identical Cre (KspCre) results in aggressive or very mild PKD, respectively. Unexpectedly, we find that mTORC1 negatively regulates the biogenesis of polycystin-1 (PC-1) and trafficking of the PC-1/2 complex to cilia. Genetic interaction studies reveal an important role for PC-1 downregulation by mTORC1 in the cystogenesis of Tsc1 mutants. Our data potentially explain the severe renal manifestations of the TSC/PKD contiguous gene syndrome and open new perspectives for the use of mTOR inhibitors in autosomal dominant PKD caused by hypomorphic or missense PKD1 mutations.

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