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PMID: 17251353 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Glomerulocystic kidney disease in mice with a targeted inactivation of Wwtr1.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 104 ·No. 5 ·2007-01-30 ·Pages 1631-6

Hossain Z, Ali SM, Ko HL, Xu J, Ng CP, Guo K, Qi Z, Ponniah S, Hong W, Hunziker W

Abstract

Wwtr1 is a widely expressed 14-3-3-binding protein that regulates the activity of several transcription factors involved in development and disease. To elucidate the physiological role of Wwtr1, we generated Wwtr1-/- mice by homologous recombination. Surprisingly, although Wwtr1 is known to regulate the activity of Cbfa1, a transcription factor important for bone development, Wwtr1-/- mice show only minor skeletal defects. However, Wwtr1-/- animals present with renal cysts that lead to end-stage renal disease. Cysts predominantly originate from the dilation of Bowman's spaces and atrophy of glomerular tufts, reminiscent of glomerulocystic kidney disease in humans. A smaller fraction of cysts is derived from tubules, in particular the collecting duct (CD). The corticomedullary accumulation of cysts also shows similarities with nephronophthisis. Cells lining the cysts carry fewer and shorter cilia and the expression of several genes associated with glomerulocystic kidney disease (Ofd1 and Tsc1) or encoding proteins involved in cilia structure and/or function (Tg737, Kif3a, and Dctn5) is decreased in Wwtr1-/- kidneys. The loss of cilia integrity and the down-regulation of Dctn5, Kif3a, Pkhd1 and Ofd1 mRNA expression can be recapitulated in a renal CD epithelial cell line, mIMCD3, by reducing Wwtr1 protein levels using siRNA. Thus, Wwtr1 is critical for the integrity of renal cilia and its absence in mice leads to the development of renal cysts, indicating that Wwtr1 may represent a candidate gene for polycystic kidney disease in humans.

MeSH Terms
14-3-3 Proteins/genetics,physiology Adaptor Proteins, Signal Transducing Alleles Animals Cell Line Down-Regulation Gene Expression Regulation Kidney/metabolism Kidney Diseases, Cystic/genetics,metabolism Mice Mice, Transgenic Models, Genetic Proteins/genetics RNA, Small Interfering/metabolism Recombination, Genetic Trans-Activators Tuberous Sclerosis Complex 1 Protein Tumor Suppressor Proteins/genetics
Chemicals
14-3-3 Proteins Adaptor Proteins, Signal Transducing OFD1 protein, mouse Proteins RNA, Small Interfering TSC1 protein, human Trans-Activators Tsc1 protein, mouse Tuberous Sclerosis Complex 1 Protein Tumor Suppressor Proteins Wwtr1 protein, mouse
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Hossain Zakir
Epithelial Cell Biology Laboratory, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Republic of Singapore 138673.
Ali Safiah Mohamed
Ko Hui Ling
Xu Jianliang
Ng Chee Peng
Guo Ke
Qi Zeng
Ponniah Sathivel
Hong Wanjin
Hunziker Walter
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0605266104
Published
2007-01-30
Epub
2007-00-24
Pages
1631-6
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1785239
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.0605266104 PMC Full Text View journal details
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