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.

MTORC1-mediated inhibition of polycystin-1 expression drives renal cyst formation in tuberous sclerosis complex / M. Pema, L. Drusian, M. Chiaravalli, M. Castelli, Q. Yao, S. Ricciardi, S. Somlo, F. Qian, S. Biffo, A. Boletta. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 7(2016), pp. 10786.1-10786.11.

MTORC1-mediated inhibition of polycystin-1 expression drives renal cyst formation in tuberous sclerosis complex

S. Ricciardi;S. Biffo;
2016

Abstract

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.
animals; cilia; cysts; down-regulation; gene expression regulation; gene silencing; mice; multiprotein complexes; polycystic kidney diseases; sirolimus; TOR serine-threonine kinases; TRPP cation channels; tuberous sclerosis; up-regulation; biochemistry, genetics and molecular biology (all); chemistry (all); physics and astronomy (all)
Settore BIO/06 - Anatomia Comparata e Citologia
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/492807
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