A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1

被引:316
作者
Piontek, Klaus
Menezes, Luis F.
Garcia-Gonzalez, Miguel A.
Huso, David L.
Germino, Gregory G.
机构
[1] Johns Hopkins Univ, Sch Med, Dept Med, Div Nephrol, Baltimore, MD 21205 USA
[2] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD 21205 USA
[3] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21205 USA
[4] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA
基金
美国国家卫生研究院;
关键词
D O I
10.1038/nm1675
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Autosomal dominant polycystic kidney disease is an important cause of end-stage renal disease, for which there is no proven therapy(1). Mutations in PKD1 (the gene encoding polycystin-1) are the principal cause of this disease. The disease begins in utero(2) and is slowly progressive, but it is not known whether cystogenesis is an ongoing process during adult life. We now show that inactivation of Pkd1 in mice before postnatal day 13 results in severely cystic kidneys within 3 weeks, whereas inactivation at day 14 and later results in cysts only after 5 months. We found that cellular proliferation was not appreciably higher in cystic specimens than in age-matched controls, but the abrupt change in response to Pkd1 inactivation corresponded to a previously unrecognized brake point during renal growth and significant changes in gene expression. These findings suggest that the effects of Pkd1 inactivation are defined by a developmental switch that signals the end of the terminal renal maturation process. Our studies show that Pkd1 regulates tubular morphology in both developing and adult kidney, but the pathologic consequences of inactivation are defined by the organ's developmental status. These results have important implications for clinical understanding of the disease and therapeutic approaches.
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收藏
页码:1490 / 1495
页数:6
相关论文
共 30 条
[1]   Gene Ontology: tool for the unification of biology [J].
Ashburner, M ;
Ball, CA ;
Blake, JA ;
Botstein, D ;
Butler, H ;
Cherry, JM ;
Davis, AP ;
Dolinski, K ;
Dwight, SS ;
Eppig, JT ;
Harris, MA ;
Hill, DP ;
Issel-Tarver, L ;
Kasarskis, A ;
Lewis, S ;
Matese, JC ;
Richardson, JE ;
Ringwald, M ;
Rubin, GM ;
Sherlock, G .
NATURE GENETICS, 2000, 25 (01) :25-29
[2]   HEREDITARY POLYCYSTIC KIDNEY-DISEASE (ADULT FORM) - MICRO-DISSECTION STUDY OF 2 CASES AT AN EARLY STAGE OF DISEASE [J].
BAERT, L .
KIDNEY INTERNATIONAL, 1978, 13 (06) :519-525
[3]   Autosomal dominant polycystic kidney disease (ADPKD, MIM 173900, PKD1 and PKD2 genes, protein products known as polycystin-1 and polycystin-2) [J].
Boucher, C ;
Sandford, R .
EUROPEAN JOURNAL OF HUMAN GENETICS, 2004, 12 (05) :347-354
[4]   Long-lasting arrest of murine polycystic kidney disease with CDK inhibitor roscovitine [J].
Bukanov, Nikolay O. ;
Smith, Laurie A. ;
Klinger, Katherine W. ;
Ledbetter, Steven R. ;
Ibraghimov-Beskrovnaya, Oxana .
NATURE, 2006, 444 (7121) :949-952
[5]  
Calvet J P, 1994, Curr Opin Nephrol Hypertens, V3, P340, DOI 10.1097/00041552-199405000-00017
[6]   Haploinsufficiency of Pkd2 is associated with increased tubular cell proliferation and interstitial fibrosis in two murine Pkd2 models [J].
Chang, Ming Yang ;
Parker, Emma ;
Ibrahim, Salwa ;
Shortland, John R. ;
Nahas, Meguid El ;
Haylor, John L. ;
Ong, Albert C. M. .
NEPHROLOGY DIALYSIS TRANSPLANTATION, 2006, 21 (08) :2078-2084
[7]   PEA3 transcription factors are expressed in tissues undergoing branching morphogenesis and promote formation of duct-like structures by mammary epithelial cells in vitro [J].
Chotteau-Lelievre, A ;
Montesano, R ;
Soriano, J ;
Soulie, P ;
Desbiens, X ;
de Launoit, Y .
DEVELOPMENTAL BIOLOGY, 2003, 259 (02) :241-257
[8]   Planar cell polarity signalling couples cell division and morphogenesis during neurulation [J].
Ciruna, B ;
Jenny, A ;
Lee, D ;
Mlodzik, M ;
Schier, AF .
NATURE, 2006, 439 (7073) :220-224
[9]   Disruption of intraflagellar in adult mice leads to transport obesity and slow-onset cystic kidney disease [J].
Davenport, James R. ;
Watts, Amanda J. ;
Roper, Venus C. ;
Croyle, Mandy J. ;
van Groen, Thomas ;
Wyss, J. Michael ;
Nagy, Tim R. ;
Kesterson, Robert A. ;
Yoder, Bradley K. .
CURRENT BIOLOGY, 2007, 17 (18) :1586-1594
[10]   DAVID: Database for annotation, visualization, and integrated discovery [J].
Dennis, G ;
Sherman, BT ;
Hosack, DA ;
Yang, J ;
Gao, W ;
Lane, HC ;
Lempicki, RA .
GENOME BIOLOGY, 2003, 4 (09)