Kidney-specific inactivation of Ofd1 leads to renal cystic disease associated with upregulation of the mTOR pathway.
The oral-facial-digital type I syndrome (OFDI; MIM 311200) is a rare syndromic form of inherited renal cystic disease. It is transmitted as an X-linked dominant, male lethal disorder and is caused by mutations in the OFD1 gene. Previous studies demonstrated that OFDI belongs to the growing number of disorders ascribed to dysfunction of primary cilia. We generated a conditional inactivation of the mouse Ofd1 gene using the Ksp-Cre transgenic line, which resulted in a viable model characterized by renal cystic disease and progressive impairment of renal function. The study of this model allowed us to demonstrate that primary cilia initially form and then disappear after the development of cysts, suggesting that the absence of primary cilia is a consequence rather than the primary cause of renal cystic disease. Immunofluorescence and western blotting analysis revealed upregulation of the mTOR pathway in both dilated and non-dilated renal structures. Treatment with rapamycin, a specific inhibitor of the mTOR pathway, resulted in a significant reduction in the number and size of renal cysts and a decrease in the cystic index compared with untreated mutant animals, suggesting that dysregulation of this pathway in our model is mTOR-dependent. The animal model we have generated could thus represent a valuable tool to understand the molecular link between mTOR and cyst development, and eventually to the identification of novel drug targets for renal cystic disease.
Zullo
Alessandro
A
Telethon Institute of Genetics and Medicine, via P. Castellino 111, 80131 Naples, Italy.
Iaconis
Daniela
D
Barra
Adriano
A
Cantone
Alessandra
A
Messaddeq
Nadia
N
Capasso
Giovanbattista
G
Dollé
Pascal
P
Igarashi
Peter
P
Franco
Brunella
B
D000818:Animals; D002478:Cells, Cultured; D002923:Cilia / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D004285:Dogs; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D020868:Gene Silencing / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D052177:Kidney Diseases, Cystic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases; D015854:Up-Regulation
D047908:Intracellular Signaling Peptides and Proteins; C508360:OFD1 protein, mouse; D011506:Proteins; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases
Nephrol Dial Transplant. 2009 Aug;24(8):2349-53
19321761
Nat Med. 2007 Dec;13(12):1490-5
17965720
Development. 2009 Sep;136(17):3019-30
19666828
EMBO J. 2004 Apr 7;23(7):1657-68
15029248
Mol Biol Cell. 2002 Sep;13(9):3096-106
12221118
Hum Mutat. 2008 Feb;29(2):289-98
18022865
Nephrol Dial Transplant. 1998 Mar;13(3):763-6
9550664
J Am Soc Nephrol. 2002 Jul;13(7):1837-46
12089379
Development. 2000 Jun;127(11):2347-55
10804177
J Cell Biol. 2000 Oct 30;151(3):709-18
11062270
Gene. 2008 May 31;415(1-2):60-7
18403135
J Clin Invest. 2004 Mar;113(6):814-25
15067314
J Am Soc Nephrol. 2004 Jul;15(7):1744-55
15213262
Nat Genet. 2003 Aug;34(4):355-6
12923538
Pathogenetics. 2009 Oct 28;2(1):6
19863783
BMC Nephrol. 2007 Sep 15;8:13
17868472
Nephron Exp Nephrol. 2007;106(3):e88-96
17519557
Annu Rev Genomics Hum Genet. 2006;7:125-48
16722803
Nat Genet. 2006 Jan;38(1):112-7
16311594
Dev Dyn. 2008 Aug;237(8):1960-71
18366137
Hum Mutat. 2008 Oct;29(10):1237-46
18546297
J Am Soc Nephrol. 2007 May;18(5):1381-8
17429051
Cell. 2001 May 4;105(3):357-68
11348592
N Engl J Med. 1964 Nov 19;271:1073-8
14210999
J Am Soc Nephrol. 2005 Jan;16(1):46-51
15563559
Nephrol Dial Transplant. 1997 May;12(5):1040-2
9175067
Am J Physiol. 1994 May;266(5 Pt 2):F767-74
7515582
Mol Biol Cell. 2001 Mar;12(3):589-99
11251073
J Am Soc Nephrol. 2004 Oct;15(10):2556-68
15466260
Mamm Genome. 2003 Apr;14(4):242-9
12682776
Hum Mol Genet. 2008 Jun 1;17(11):1505-16
18263604
Trends Cell Biol. 2003 Sep;13(9):484-92
12946628
Nephrol Dial Transplant. 2006 Mar;21(3):598-604
16221708
J Biol Chem. 2002 Aug 9;277(32):29028-35
12006559
PLoS One. 2008;3(10):e3581
18974783
Development. 2006 Nov;133(21):4131-43
17021045
Nat Cell Biol. 2002 Sep;4(9):648-57
12172553
Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18722-7
19850877
J Am Soc Nephrol. 2003 Mar;14(3):680-9
12595504
Hum Mol Genet. 2009 Nov 15;18(22):4428-41
19692352
Kidney Int. 2003 Apr;63(4):1220-9
12631338
Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9784-9
11493697
Mol Biol Cell. 2007 Nov;18(11):4397-404
17761535
Hum Mol Genet. 2009 Jan 1;18(1):151-63
18845692
Hum Mol Genet. 2007 Dec 15;16(24):3188-96
17932118
Curr Top Dev Biol. 2008;85:371-427
19147012
Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5286-91
12672950
Nephrol Dial Transplant. 1997 Jul;12(7):1354-61
9249769
J Am Soc Nephrol. 2002 Oct;13(10):2508-16
12239239
Nat Rev Genet. 2005 Dec;6(12):928-40
16341073
Biochem Soc Trans. 2003 Jun;31(Pt 3):584-6
12773160
Am J Med Genet C Semin Med Genet. 2009 Nov 15;151C(4):318-25
19876934
J Biol Chem. 1995 Jan 13;270(2):815-22
7822316
Hum Mol Genet. 2009 Feb 15;18(4):595-606
19008302
Proc Natl Acad Sci U S A. 2006 Apr 4;103(14):5466-71
16567633
Nephrology (Carlton). 2007 Dec;12(6):559-64
17995581