Renal

We focus primarily on the molecular biology, molecular genetics and developmental biology of a novel class of integral membrane proteins, so called polycystins, and the molecular mechanisms underlying cyst formation in polycystic kidney disease.

Currently, there are seven members of the polycystin family. Mutations in two of them, polycystin-1 and -2, cause autosomal dominant polycystic kidney disease (ADPKD), characterized by progressive development of epithelial cysts in the kidney, which ultimately leads to renal failure. Our laboratory has isolated six of the seven polycystins. By gene targeting we have shown that polycystin-1 and -2 are critical in development, particularly in the development of the kidney, pancreas and cartilage. Using electrophysiological approaches we have shown that polycystin-2 and -L function as Ca2+-permeable cation channels that may mediate Ca2+ release or Ca2+ influx. Very recently, we have shown that polycystin-1 functions as a G-protein coupled receptor and its function is regulated by polycystin-2.

The current focus of the lab is on the biological function of polycystins and the signaling pathways they take part in. Ongoing projects include further biochemical characterization of polycystins, identification of polycystin interacting proteins and generation of polycystin-deficient cell and animal models as well as identification of genetic modifier gene(s) of ADPKD.

http://zhou-lab.bwh.harvard.edu/index.html

Recent Publications

1. Lu WN, Fan XH, Basora N, Babakhanlou H, Law T, Rifai N, Harris PC, Perez-Atayde AR, Rennke HG and Zhou J. Late onset of renal and hepatic cysts in mice heterozygous for a targetted Pkd1 mutation. Nature Genetics 1999, 21(2):160-161.
   
   
2. Chen, XZ, Vassilev, PM, Basora, N, Peng, JP, Nomura, N, Segal, Y, Brown, EB, Reeders, ST, Hediger, MA, and Zhou, J. Polycystin-L, a member of the polycystin family of proteins, is a calcium-permeable cation channel. Nature, 1999, 401, 383-386.
   
   
3. Guo, L, Chen, MH, Basora, N, and Zhou, J. The human polycystic kidney disease 2-like (PKDL) gene: exon/intron structure and evidence for a novel splicing mechanism. Mammalian Genome, 2000 Jan;11(1):46-50.
   
   
4. Guo L, Schreiber TH, Weremowicz S, Morton CC, and Zhou J. Molecular cloning and characterization of a novel polycystin family member, polycystin-l2, in mouse and man. Genomics. 2000, Mar:64,241-251.
   
   
5. Pritchard L, Sloane-Stanley J, Sharp J, Alpers CE, Lu W, Zhou J, Wood W, and Harris P. A human PKD1 transgene generates functional polycystin-1 in mice and is associated with a cystic phenotype. Hum Mol Genetics 2000 Nov 1;9(18):2617-2627.
   
   
6. Segal Y, Rondeau E and Zhou J. Identification of cis-acting elements and promoter configuration of the type IV collagen gene COL4A5 and COL4A6. J. Biol. Chem, 2001 Apr 13;276(15):11791-7.
   
   
7. Chen XZ, Segal Y, Basora N, Guo L, Peng JB, Babakhanlou H, Vassilev P, Brown EM, Hediger MA, and Zhou J. The transport function of the naturally occurring pathogenic polycystin-2 mutant, R742X. Biochem Biophys Res Commun 2001 Apr 20;282(5):1251-6.
   
   
8. Vassilev P, Guo L, Chen XZ, Segal Y, Peng JB, Basora N, Babakhanlou H, Cruger G, Kanazirska M, Ye CP, Brown EM, Hediger MA, and Zhou J. Polycystic kidney disease 2 gene encodes a novel high conductance channel implicated in defective intracellular Ca2+ homeostasis. Biochem Biophys Res Commun 2001, Mar 23;282(1):341-350.
   
   
9. Stayner C and Zhou J: Polycystin channels and kidney disease. Trends in Pharmacological Sciences, 2001, 22 (11) 543-546.
   
   
10. Lu WN, Shen X, Pavlova A, Lakkis M, Ward C, Pritchard L, Harris P, Genest D, Perez-Atayde A, and Zhou J. Comparison of Pkd1-targeted mutants reveals that loss of polycystin-1 causes cystogenesis and bone defects. Hum Mol Genetics. 2001, Oct 2;10(21):2385-2396.
    
    
11. Basora N, Nomura H, Berger U, Stayner C, Guo L, Shen XH, and Zhou J. Tissue and cellular localization of a novel polycystic kidney disease-like gene product, polycystin-L. J Am Soc Nephrol 2002 Feb;13(2):293-301.
    
    
12. Delmas P, Nomura H, Li X, Lakkis M, Luo Y, Segal Y, Fernández-Fernández J, Harris P, Frischauf AM, Brown DA and Zhou J. Constitutive activation of G-proteins by polycystin-1 is antagonized by polycystin-2. J. Biol. Chem, in press, 2002.
    
    
13. Yuasa T, Venugopal B, Weremowicz S, Morton CC, Guo L, and Zhou J. A Novel Polycystic Kidney Disease 1 Like Gene, PKD1L1, in Human: Sequence, Expression, and Chromosomal Localization. Genomics, 2002 Mar;79(3):376-86.