Polycystin-2 Expression Is Regulated by a PC2-binding Domain in the Intracellular Portion of Fibrocystin

Autosomal dominant (ADPKD) and autosomal recessive (ARPKD) polycystic kidney disease are caused by mutations in Pkd1/Pkd2 and Pkhd1, which encode polycystins (PCs) and fibrocystin/polyductin (FPC). Our recent study reported that a deficiency in FPC increases the severity of cystic disease in Pkd2 mutants and down-regulates PC2 in vivo, but the precise molecular mechanism of these effects is unknown (Kim, I., Fu, Y., Hui, K., Moeckel, G., Mai, W., Li, C., Liang, D., Zhao, P., Ma, J., Chen, X.-Z., George, A. L., Jr., Coffey, R. J., Feng, Z. P., and Wu, G. (2008) J. Am. Soc. Nephrol. 19, 455–468). In this study, through the use of deletion and mutagenesis strategies, we identified a PC2-binding domain in the intracellular C terminus of FPC and an FPC-binding domain in the intracellular N terminus of PC2. These binding domains provide a molecular basis for the physical interaction between PC2 and FPC. In addition, we also found that physical interaction between the binding domains of PC2 and FPC is able to prevent down-regulation of PC2 induced by loss of FPC. In vivo, we generated a mouse model of ADPKD with hypomorphic Pkd2 alleles (Pkd2nf3/nf3) and show that PC2 down-regulation is accompanied by a phenotype similar to that of Pkhd1–/– mice. These findings demonstrate a common mechanism underlying cystogenesis in ADPKD and ARPKD and provide insight into the molecular relationship between PC2 and FPC. Autosomal dominant (ADPKD) and autosomal recessive (ARPKD) polycystic kidney disease are caused by mutations in Pkd1/Pkd2 and Pkhd1, which encode polycystins (PCs) and fibrocystin/polyductin (FPC). Our recent study reported that a deficiency in FPC increases the severity of cystic disease in Pkd2 mutants and down-regulates PC2 in vivo, but the precise molecular mechanism of these effects is unknown (Kim, I., Fu, Y., Hui, K., Moeckel, G., Mai, W., Li, C., Liang, D., Zhao, P., Ma, J., Chen, X.-Z., George, A. L., Jr., Coffey, R. J., Feng, Z. P., and Wu, G. (2008) J. Am. Soc. Nephrol. 19, 455–468). In this study, through the use of deletion and mutagenesis strategies, we identified a PC2-binding domain in the intracellular C terminus of FPC and an FPC-binding domain in the intracellular N terminus of PC2. These binding domains provide a molecular basis for the physical interaction between PC2 and FPC. In addition, we also found that physical interaction between the binding domains of PC2 and FPC is able to prevent down-regulation of PC2 induced by loss of FPC. In vivo, we generated a mouse model of ADPKD with hypomorphic Pkd2 alleles (Pkd2nf3/nf3) and show that PC2 down-regulation is accompanied by a phenotype similar to that of Pkhd1–/– mice. These findings demonstrate a common mechanism underlying cystogenesis in ADPKD and ARPKD and provide insight into the molecular relationship between PC2 and FPC. Autosomal dominant polycystic kidney disease (ADPKD) 2The abbreviations used are: ADPKD, autosomal dominant polycystic kidney disease; ARPKD, autosomal recessive polycystic kidney disease; PC, polycystin; FPC, fibrocystin/polyductin; FBD, FPC-binding domain; PC2BD, PC2-binding domain; HA, hemagglutinin; co-IP, co-immunoprecipitation. 2The abbreviations used are: ADPKD, autosomal dominant polycystic kidney disease; ARPKD, autosomal recessive polycystic kidney disease; PC, polycystin; FPC, fibrocystin/polyductin; FBD, FPC-binding domain; PC2BD, PC2-binding domain; HA, hemagglutinin; co-IP, co-immunoprecipitation. is characterized by numerous fluid-filled, spherical renal cysts, and autosomal recessive polycystic kidney disease (ARPKD) is characterized by massive, spindle-shaped renal cysts (1Igarashi P. Somlo S. J. Am. Soc. Nephrol. 2002; 13: 2384-2398Crossref PubMed Scopus (437) Google Scholar, 2Wilson P. N. Engl. J. Med. 2004; 350: 151-164Crossref PubMed Scopus (604) Google Scholar). The causal genes for both ADPKD and ARPKD have been identified (3The European Polycystic Kidney Disease ConsortiumCell. 1994; 77: 881-894Abstract Full Text PDF PubMed Scopus (743) Google Scholar, 4Mochizuki T. Wu G. Hayashi T. Xenophontos S.L. Veldhuisen B. Saris J.J. Reynolds D.M. Cai Y. Gabow P.A. Pierides A. Kimberling W.J. Breuning M.H. Deltas C.C. Peters D.J. Somlo S. Science. 1996; 272: 1339-1342Crossref PubMed Scopus (1149) Google Scholar, 5Ward C.J. Hogan M.C. Rossetti S. Walker D. Sneddon T. Wang X. Kubly V. Cunningham J.M. Bacallao R. Ishibashi M. Milliner D.S. Torres V.E. Harris P.C. Nat. Genet. 2002; 30: 259-269Crossref PubMed Scopus (574) Google Scholar, 6Onuchic L.F. Furu L. Nagasawa Y. Hou X. Eggermann T. Ren Z. Bergmann C. Senderek J. Esquivel E. Zeltner R. Rudnik-Schoneborn S. Mrug M. Sweeney W. Avner E.D. Zerres K. Guay-Woodford L.M. Somlo S. Germino G.G. Am. J. Hum. 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El-Youssef M. Torres V.E. Harris P.C. Kidney Int. 2003; 64: 391-403Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar, 11Sharp A.M. Messiaen L.M. Page G. Antignac C. Gubler M.C. Onuchic L.F. Somlo S. Germino G.G. Guay-Woodford L.M. J. Med. Genet. 2005; 42: 336-349Crossref PubMed Scopus (76) Google Scholar). PKD1 has a 14-kb transcript and encodes PC1, a 4303-amino acid integral membrane protein with 11 putative transmembrane domains. PC1 is expressed in all tissues and organs of humans and mice (12American PKD1 ConsortiumHum. Mol. Genet. 1995; 4: 575-582Crossref PubMed Scopus (237) Google Scholar). The N-terminal region contains an extracellular portion of >3000 amino acids, which is predicted to be a site of protein-protein or receptor-ligand interactions (2Wilson P. N. Engl. J. Med. 2004; 350: 151-164Crossref PubMed Scopus (604) Google Scholar, 13Torres V.E. Harris P.C. Nat. Clin. Pract. Nephrol. 2006; 2: 40-55Crossref PubMed Scopus (235) Google Scholar). This region may also be released after cleavage at the GPS domain of PC1 and serve as a ligand for other proteins (14Yu S. Hackmann K. Gao J. He X. Piontek K. Garcia-Gonzalez M.A. Menezes L.F. Xu H. Germino G.G. Zuo J. Qian F. Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 18688-18693Crossref PubMed Scopus (119) Google Scholar). The cytoplasmic C-terminal region of PC1 contains a putative coiled-coil domain that interacts with the PKD2 gene product, PC2 (15Qian F. Germino F.J. Cai Y. Zhang X. Somlo S. Germino G.G. Nat. Genet. 1997; 16: 179-183Crossref PubMed Scopus (549) Google Scholar). PKD2 has an ∼5.4-kb transcript and encodes PC2, a 968-amino acid protein that is predicted to be an integral membrane protein with six putative transmembrane domains and intracellular N and C termini (4Mochizuki T. Wu G. Hayashi T. Xenophontos S.L. Veldhuisen B. Saris J.J. Reynolds D.M. Cai Y. Gabow P.A. Pierides A. Kimberling W.J. Breuning M.H. Deltas C.C. Peters D.J. Somlo S. Science. 1996; 272: 1339-1342Crossref PubMed Scopus (1149) Google Scholar). PC2 is a receptor-operated, nonselective cation channel; it is also known as TRPP2, a member of the trp superfamily (16Montell C. Birnbaumer L. Flockerzi V. Cell. 2002; 108: 595-598Abstract Full Text Full Text PDF PubMed Scopus (714) Google Scholar, 17Qamar S. Vadivelu M. Sandford R. Biochem. Soc. Trans. 2007; 35: 124-128Crossref PubMed Scopus (28) Google Scholar). PKHD1 has a 16-kb transcript, contains at least 86 exons, and spans 470 kb on chromosome 6p12 (11Sharp A.M. Messiaen L.M. Page G. Antignac C. Gubler M.C. Onuchic L.F. Somlo S. Germino G.G. Guay-Woodford L.M. J. Med. Genet. 2005; 42: 336-349Crossref PubMed Scopus (76) Google Scholar). The longest open reading frame is predicted to be 66 exons and yields a 4074-amino acid type I membrane protein, FPC (5Ward C.J. Hogan M.C. Rossetti S. Walker D. Sneddon T. Wang X. Kubly V. Cunningham J.M. Bacallao R. Ishibashi M. Milliner D.S. Torres V.E. Harris P.C. Nat. Genet. 2002; 30: 259-269Crossref PubMed Scopus (574) Google Scholar, 6Onuchic L.F. Furu L. Nagasawa Y. Hou X. Eggermann T. Ren Z. Bergmann C. Senderek J. Esquivel E. Zeltner R. Rudnik-Schoneborn S. Mrug M. Sweeney W. Avner E.D. Zerres K. Guay-Woodford L.M. Somlo S. Germino G.G. Am. J. Hum. Genet. 2002; 70: 1305-1317Abstract Full Text Full Text PDF PubMed Scopus (375) Google Scholar, 7Xiong H. Chen Y. Yi Y. Tsuchiya K. Moeckel G. Cheung J. Liang D. Tham K. Xu X. Chen X.-Z. Pei Y. Zhao Z.J. Wu G. Genomics. 2002; 80: 96-104Crossref PubMed Scopus (60) Google Scholar). The cytoplasmic C-terminal region of FPC is composed of 192 amino acids. FPC is predicted to be a membrane-associated, receptor-like protein. In addition, cleavage and release of its ectodomain into the renal tubular/duct lumen have been reported (5Ward C.J. Hogan M.C. Rossetti S. Walker D. Sneddon T. Wang X. Kubly V. Cunningham J.M. Bacallao R. Ishibashi M. Milliner D.S. Torres V.E. Harris P.C. Nat. Genet. 2002; 30: 259-269Crossref PubMed Scopus (574) Google Scholar, 18Kaimori J.Y. Nagasawa Y. Menezes L.F. Garcia-Gonzalez M.A. Deng J. Imai E. Onuchic L.F. Guay-Woodford L.M. Germino G.G. Hum. Mol. Genet. 2007; 16: 942-956Crossref PubMed Scopus (80) Google Scholar). Several recent reports have demonstrated functional and genetic relationships between FPC and the PCs (19Wu Y. Dai X.Q. Li Q. Chen C.X. W. Z. W. N. Li G. R. Wang S. Wu G. Chen X.-Z. Hum. Mol. Genet. 2006; PubMed Scopus Google Scholar, M.A. Menezes L.F. Piontek J. D.L. T. Onuchic L.F. Guay-Woodford L.M. Germino G.G. Hum. Mol. Genet. 2007; 16: PubMed Scopus Google Scholar, S. Zhang J. Li X. Y. J. Mol. Cell. 2007; PubMed Scopus Google Scholar, Y. K. Moeckel G. W. Li C. Liang D. Zhao P. J. Chen X.-Z. Jr., Wu G. J. Am. Soc. Nephrol. PubMed Scopus Google Scholar). Wu (19Wu Y. Dai X.Q. Li Q. Chen C.X. W. Z. W. N. Li G. R. Wang S. Wu G. Chen X.-Z. Hum. Mol. Genet. 2006; PubMed Scopus Google have demonstrated that a of the is able to FPC and PC2 The of the PC2 is the binding is has also been reported that FPC which may be induced by PC2 S. Zhang J. Li X. Y. J. Mol. Cell. 2007; PubMed Scopus Google and that loss of FPC down-regulates PC2 in Y. K. Moeckel G. W. Li C. Liang D. Zhao P. J. Chen X.-Z. Jr., Wu G. J. Am. Soc. Nephrol. PubMed Scopus Google Scholar). In addition, loss of FPC the cystic phenotype of a genetic interaction between FPC and PC1 M.A. Menezes L.F. Piontek J. D.L. T. Onuchic L.F. Guay-Woodford L.M. Germino G.G. Hum. Mol. Genet. 2007; 16: PubMed Scopus Google Scholar). These findings a functional relationship between FPC and PCs in vivo, the underlying molecular are the molecular relationships between these we the molecular interaction between PC2 and FPC. gene deletion and we identified an FPC-binding domain in the intracellular N terminus of PC2 and a PC2-binding domain in the intracellular C terminus of FPC. This physical interaction PC2 down-regulation induced by loss of FPC Y. K. Moeckel G. W. Li C. Liang D. Zhao P. J. Chen X.-Z. Jr., Wu G. J. Am. Soc. Nephrol. PubMed Scopus Google Scholar). mice a to of which to down-regulation of PC2, have a phenotype similar to that of mice. This model that the of spherical cysts, in ADPKD, and the spindle-shaped of in ARPKD, are induced by a common These findings the for PC2 and FPC in the of both ADPKD and ARPKD and a between ARPKD and have reported the of the mouse model for Y. K. Moeckel G. W. Li C. Liang D. Zhao P. J. Chen X.-Z. Jr., Wu G. J. Am. Soc. Nephrol. PubMed Scopus Google Scholar). have generated a model in which a as a by and to of Pkd2 and found to after a of and This by and into at the of and mouse used in this study have been the and and used to and Pkd2 mice Y. K. Moeckel G. W. Li C. Liang D. Zhao P. J. Chen X.-Z. Jr., Wu G. J. Am. Soc. Nephrol. PubMed Scopus Google Scholar, G. X. Cai Y. G. V. L. Li L. L. Zhao H. W. Somlo S. Hum. Mol. Genet. 2002; PubMed Scopus Google Scholar). or the of exons of the with and with of in these used as a the with the of the of Pkd2 and FPC and PC2 and in (19Wu Y. Dai X.Q. Li Q. Chen C.X. W. Z. W. N. Li G. R. Wang S. Wu G. Chen X.-Z. Hum. Mol. Genet. 2006; PubMed Scopus Google Scholar, W. Li C. C. Moeckel G. Zhao R. Wang J. H. Wang H. Y. Wu Y. Y. M. Pei Y. Harris Li S. L. Wu D. Chen X.-Z. Zhao Z.J. Wu G. Proc. Natl. Acad. Sci. U. S. A. 2004; PubMed Scopus Google Scholar). the intracellular N terminus of PC2 and The and and and and and and similar to in study W. Li C. C. Moeckel G. Zhao R. Wang J. H. Wang H. Y. Wu Y. Y. M. Pei Y. Harris Li S. L. Wu D. Chen X.-Z. Zhao Z.J. Wu G. Proc. Natl. Acad. Sci. U. S. A. 2004; PubMed Scopus Google Scholar). binding in used to the The intracellular termini and the deletion of FPC and PC2 in and Z. M. Z. B. W. Wu Y. Wu G. Li L. M. Wu D. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google and are in and The intracellular C terminus of PC2 of the of the intracellular C terminus of of and C-terminal of FPC and an intracellular N-terminal of PC2. acid are in with PC2 are with for binding and for of of with or of with and of the used as for and for that with and of with or The for and for that and with but and show the of protein by and for and for similar to in C. of and mouse a the site in is of with or The a of the of protein by The for and for that with but the and for and W. Li C. C. Moeckel G. Zhao R. Wang J. H. Wang H. Y. Wu Y. Y. M. Pei Y. Harris Li S. L. Wu D. Chen X.-Z. Zhao Z.J. Wu G. Proc. Natl. Acad. Sci. U. S. A. 2004; PubMed Scopus Google Scholar). a with and and Kidney used in this study W. Chen D. T. S. S. Liang D. Wang N. Wu D. Li S. Zhao P. R. Wu G. Mol. Cell. 2005; 16: PubMed Scopus Google Scholar). The and of renal Pkhd1–/– and in study Y. K. Moeckel G. W. Li C. Liang D. Zhao P. J. Chen X.-Z. Jr., Wu G. J. Am. Soc. Nephrol. PubMed Scopus Google Scholar). and B. used to FPC and and to Pkhd1–/– by the and after of for M.A. J. Reynolds A.B. Cell. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). to or of by with of an in the N of for a physical interaction between the intracellular N terminus of PC2 and the C terminus of FPC reported Y. K. Moeckel G. W. Li C. Liang D. Zhao P. J. Chen X.-Z. Jr., Wu G. J. Am. Soc. Nephrol. PubMed Scopus Google but the precise of this interaction is we a to the domains in the interaction between PC2 and FPC. we generated both and and that the intracellular portion of FPC. also a of deletion of the intracellular N terminus of PC2 used of the N terminus of PC2 and to with the C terminus of FPC into of the PC2 N terminus with used as a Y. K. Moeckel G. W. Li C. Liang D. Zhao P. J. Chen X.-Z. Jr., Wu G. J. Am. Soc. Nephrol. PubMed Scopus Google Scholar). for the and the but for the that the portion of the N terminus of PC2 is in the we the and to with FPC a for the intracellular C terminus of FPC W. Li C. C. Moeckel G. Zhao R. Wang J. H. Wang H. Y. Wu Y. Y. M. Pei Y. Harris Li S. L. Wu D. Chen X.-Z. Zhao Z.J. Wu G. Proc. Natl. Acad. Sci. U. S. A. 2004; PubMed Scopus Google Scholar). These that the portion of the N terminus of PC2 but the portion is in the binding between FPC and PC2 the of PC2, we generated a of deletion for with for the and but for the and These that the amino acid the contains the of PC2. we used for and for and the these we the and to with FPC as similar as in these that of PC2 may as an used a to that the N terminus of PC2 FPC. generated the mutations the region of PC2, The a that with is a predicted protein C site (4Mochizuki T. Wu G. Hayashi T. Xenophontos S.L. Veldhuisen B. Saris J.J. Reynolds D.M. Cai Y. Gabow P.A. Pierides A. Kimberling W.J. Breuning M.H. Deltas C.C. Peters D.J. Somlo S. Science. 1996; 272: 1339-1342Crossref PubMed Scopus (1149) Google Scholar). The an the may the of the as demonstrated that FPC but This that the of PC2 to the intracellular C terminus of FPC. the of the PC2, we generated a in which the binding domain for FPC, that deletion of this region FPC binding to PC2 that is the of PC2. of a in the of the of the intracellular N terminus of PC2 we used a similar to the of the intracellular C terminus of FPC. used of the C terminus of FPC and to with the N terminus of PC2 into of the FPC C terminus with used as a of the intracellular C terminus of PC2 with as as other used as a for the and the but for the or the These that the of the C terminus of FPC is in the the of FPC, we generated a of deletion the intracellular C terminus of FPC for with for the and but for the or and These that is the for the of FPC. these we the and to with PC2 a for the intracellular C terminus of PC2 the N terminus of PC2 to but to or may as a we used a to that the PC2. generated a that an The is and in both and mouse FPC. of this predicted to the of the and used to PC2, and used for The FPC binding to PC2 for physical interaction between the intracellular C terminus of FPC and the intracellular N terminus of PC2. FPC to PC2 PC2 have reported that loss of FPC PC2 in Y. K. Moeckel G. W. Li C. Liang D. Zhao P. J. Chen X.-Z. Jr., Wu G. J. Am. Soc. Nephrol. PubMed Scopus Google but the mechanism by which this the basis of the findings we that the physical interaction between the C terminus of FPC and the N terminus of PC2 is in the of PC2 we used of renal and Pkhd1–/– Y. K. Moeckel G. W. Li C. Liang D. Zhao P. J. Chen X.-Z. Jr., Wu G. J. Am. Soc. Nephrol. PubMed Scopus Google to loss of FPC PC2 in the that loss of FPC PC2 protein and we Pkhd1–/– in with which contains the intracellular C terminus of FPC These demonstrated a of PC2 and that physical interaction between the C terminus of FPC and the N terminus of PC2 the down-regulation of PC2 induced by loss of FPC. this we Pkhd1–/– with which contains the PC2BD, and similar C and These that the interaction of FPC and PC2 the down-regulation of PC2 induced by loss of FPC. In of PC2 of the molecular interaction between FPC and PC2, we used a mouse a hypomorphic Pkd2 in which a to of Pkd2 down-regulates PC2 by a and The hypomorphic alleles in Pkd2 (Pkd2nf3/nf3) Pkd2 and PC2 to of mice PC2 able to and of the In addition, of the common of mice with the in a of mice cystic and in the and similar in to in Pkhd1–/– mice and The severity of cysts and the at disease mice. of the mice by all cystic in the and or also in the and and of mice. These of Pkhd1–/– massive, renal and of with a and of The that down-regulation of Pkd2 the in that FPC and PC2 are and that the down-regulation of in similar cystic in the the genetic and functional relationships between the ADPKD and ARPKD causal gene and FPC, have been reported (19Wu Y. Dai X.Q. Li Q. Chen C.X. W. Z. W. N. Li G. R. Wang S. Wu G. Chen X.-Z. Hum. Mol. Genet. 2006; PubMed Scopus Google Scholar, M.A. Menezes L.F. Piontek J. D.L. T. Onuchic L.F. Guay-Woodford L.M. Germino G.G. Hum. Mol. Genet. 2007; 16: PubMed Scopus Google Scholar, S. Zhang J. Li X. Y. J. Mol. Cell. 2007; PubMed Scopus Google Scholar, Y. K. Moeckel G. W. Li C. Liang D. Zhao P. J. Chen X.-Z. Jr., Wu G. J. Am. Soc. Nephrol. PubMed Scopus Google the precise molecular and of the interaction between the unknown J.Y. Germino G.G. J. Am. Soc. Nephrol. PubMed Scopus Google Scholar). we used deletion and mutagenesis to a in the intracellular C terminus of FPC and an in the intracellular N terminus of PC2. These provide a molecular basis for the physical interaction between PC2 and FPC. ADPKD is characterized by spherical renal cysts, ARPKD is characterized by numerous spindle-shaped of renal (1Igarashi P. Somlo S. J. Am. Soc. Nephrol. 2002; 13: 2384-2398Crossref PubMed Scopus (437) Google Scholar, 2Wilson P. N. Engl. J. Med. 2004; 350: 151-164Crossref PubMed Scopus (604) Google Scholar). it has been that FPC and PC2 to the W. Li C. C. Moeckel G. Zhao R. Wang J. H. Wang H. Y. Wu Y. Y. M. Pei Y. Harris Li S. L. Wu D. Chen X.-Z. Zhao Z.J. Wu G. Proc. Natl. Acad. Sci. U. S. A. 2004; PubMed Scopus Google Scholar, C.J. D. Wang X. R. S. Bacallao R. Torra R. Torres V.E. Harris P.C. Hum. Mol. Genet. 2003; PubMed Scopus Google Scholar, S. Y. J. J. Am. Soc. Nephrol. 2004; PubMed Scopus Google and that are (19Wu Y. Dai X.Q. Li Q. Chen C.X. W. Z. W. N. Li G. R. Wang S. Wu G. Chen X.-Z. Hum. Mol. Genet. 2006; PubMed Scopus Google Scholar, M.A. Menezes L.F. Piontek J. D.L. T. Onuchic L.F. Guay-Woodford L.M. Germino G.G. Hum. Mol. Genet. 2007; 16: PubMed Scopus Google Scholar, S. Zhang J. Li X. Y. J. Mol. Cell. 2007; PubMed Scopus Google Scholar, Y. K. Moeckel G. W. Li C. Liang D. Zhao P. J. Chen X.-Z. Jr., Wu G. J. Am. Soc. Nephrol. PubMed Scopus Google a common lead to and In ADPKD cysts are to loss of F. Onuchic L.F. Germino G.G. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, V. Cai Y. G. Reynolds D.M. Y. Hou Jr., H. R. W. Somlo S. Cell. Full Text Full Text PDF PubMed Scopus Google in which a renal that an a at the other This to loss of PC1 or PC2 at the and that to and as as and E. E. A. F. Torres V. M. M. Nat. Genet. 2006; PubMed Scopus Google Scholar, W. Chen D. T. S. S. Liang D. Wang N. Wu D. Li S. Zhao P. R. Wu G. Mol. Cell. 2005; 16: PubMed Scopus Google Scholar, M. J.P. J. 2002; Full Text Full Text PDF PubMed Scopus Google in the of a In ARPKD, the of in both alleles in all renal by loss of FPC. the renal of ARPKD the at the In PC2 is in all of the In this PC2 a for the The that mice a similar to that of the of Pkhd1–/– mice a common molecular mechanism underlying the cystogenesis of ADPKD and Our mice are able to serve as a mouse model to study in polycystic kidney Our recent study that loss of FPC down-regulates PC2 in but that Pkd2 Y. K. Moeckel G. W. Li C. Liang D. Zhao P. J. Chen X.-Z. Jr., Wu G. J. Am. Soc. Nephrol. PubMed Scopus Google that FPC may be for PC2 protein recent that with interacts with the intracellular C terminus of PC2 and PC2 an in Y. R. J. Li D. J. R. M.B. J. T. Mol. Cell. 2007; PubMed Scopus Google Scholar). mice cystic and that may a in the of polycystic kidney disease Z. Xu J. K. Z. S. W. W. Proc. Natl. Acad. Sci. U. S. A. 2007; 104: PubMed Scopus Google Scholar). The is to be in and of proteins 2007; PubMed Scopus Google it may PC2 the basis of these we physical interaction between FPC and PC2 down-regulation of PC2. that with the are able to PC2 we that FPC PC2 by The clinical of ARPKD are K. Rudnik-Schoneborn S. Senderek J. Eggermann T. Bergmann C. J. Nephrol. 2003; 16: Google Scholar, L.M. 2003; PubMed Scopus Google Scholar). of ARPKD have disease as R. V. J. A. Guay-Woodford L.M. Nephrol. 2003; 18: PubMed Scopus Google and the is for the with ARPKD that the and of these renal disease L.M. 2003; PubMed Scopus Google Scholar, R. V. J. A. Guay-Woodford L.M. Nephrol. 2003; 18: PubMed Scopus Google Scholar, K. Rudnik-Schoneborn S. G. Nephrol. 1996; Google Scholar). In addition, ARPKD also L.M. 2003; PubMed Scopus Google as a of and disease K. Rudnik-Schoneborn S. Senderek J. Eggermann T. Bergmann C. J. Nephrol. 2003; 16: Google Scholar, L.M. 2003; PubMed Scopus Google D.L. Nephrol. 16: PubMed Scopus Google and K. Rudnik-Schoneborn S. Senderek J. Eggermann T. Bergmann C. J. Nephrol. 2003; 16: Google Scholar). we Pkhd1–/– mice Y. K. Moeckel G. W. Li C. Liang D. Zhao P. J. Chen X.-Z. Jr., Wu G. J. Am. Soc. Nephrol. PubMed Scopus Google Scholar). The for these are it is that loss of FPC may PC2 to and that this may be or for the in disease and severity with In we have identified a in the intracellular C terminus of FPC and an in the intracellular N terminus of PC2. The physical interaction between these binding domains the down-regulation of PC2 induced by loss of FPC. Our mice a similar to that by Pkhd1–/– mice. These findings provide insight into the molecular relationships between PC2 and FPC and that a common mechanism in both ARPKD and P. for and and of for mouse with

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