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.
"Western blot analyses were performed using protocols similar to those described previously , . Briefly, proteins from cultured cells or tissues were extracted in lysis buffer (0.5% NP-40, 5% Sodium deoxycholate, 50 µM NaCl, 10 µM Tris-HCl (pH 7.5), 1% BSA), homogenized and centrifuged. "
[Show abstract][Hide abstract] ABSTRACT: Bicc1 is a mouse homologue of Drosophila Bicaudal-C (dBic-C), which encodes an RNA-binding protein. Orthologs of dBic-C have been identified in many species, from C. elegans to humans. Bicc1-mutant mice exhibit a cystic phenotype in the kidney that is very similar to human polycystic kidney disease. Even though many studies have explored the gene characteristics and its functions in multiple species, the developmental profile of the Bicc1 gene product (Bicc1) in mammal has not yet been completely characterized. To this end, we generated a polyclonal antibody against Bicc1 and examined its spatial and temporal expression patterns during mouse embryogenesis and organogenesis. Our results demonstrated that Bicc1 starts to be expressed in the neural tube as early as embryonic day (E) 8.5 and is widely expressed in epithelial derivatives including the gut and hepatic cells at E10.5, and the pulmonary bronchi at E11.5. In mouse kidney development, Bicc1 appears in the early ureteric bud and mesonephric tubules at E11.5 and is also expressed in the metanephros at the same stage. During postnatal kidney development, Bicc1 expression gradually expands from the cortical to the medullary and papillary regions, and it is highly expressed in the proximal tubules. In addition, we discovered that loss of the Pkd1 gene product, polycystin-1 (PC1), whose mutation causes human autosomal dominant polycystic kidney disease (ADPKD), downregulates Bicc1 expression in vitro and in vivo. Our findings demonstrate that Bicc1 is developmentally regulated and reveal a new molecular link between Bicc1 and Pkd1.
PLoS ONE 03/2014; 9(3):e88816. DOI:10.1371/journal.pone.0088816 · 3.23 Impact Factor
"On the other hand, mice carrying one Pkd1 as well as one Pkd2 mutant allele are viable and show accelerated renal cystic disease compared to the single gene phenotypes . Also hypomorphic mouse models for polycystic kidney disease that express Pkd1 or Pkd2 at a reduced level are viable, although they develop severe PKD   . Extra-renal manifestations such as cysts in liver and pancreas [21–23,28,33–35], and aortic dissecting aneurysms have been reported as well  . "
[Show abstract][Hide abstract] ABSTRACT: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is an inherited systemic disease with intrarenal cystogenesis as its primary characteristic. A variety of mouse models provided information on the requirement of loss of balanced polycystin levels for initiation of cyst formation, the role of proliferation in cystogenesis and the signaling pathways involved in cyst growth and expansion. Here we will review the involvement of different signaling pathways during renal development, renal epithelial regeneration and cyst formation in ADPKD, focusing on planar cell polarity (PCP) and oriented cell division (OCD). This will be discussed in context of the hypothesis that aberrant PCP signaling causes cyst formation. In addition, the role of the Hippo pathway, which was recently found to be involved in cyst growth and tissue regeneration, and well-known for regulating organ size control, will be reviewed. The fact that Hippo signaling is linked to PCP signaling makes the Hippo pathway a novel cascade in cystogenesis. The newly gained understanding of the complex signaling network involved in cystogenesis and disease progression, not only necessitates refining of the current hypothesis regarding initiation of cystogenesis, but also has implications for therapeutic intervention strategies. This article is part of a Special Issue entitled: Polycystic Kidney Disease.
[Show abstract][Hide abstract] ABSTRACT: Polyzystische Nierenerkrankungen (PKD) sind der häufigste genetische Grund für ein terminales Nierenversagen. Flüssigkeitsgefüllte
Zysten bilden sich im Nierenparenchym und beeinträchtigen die Nierenfunktion mit zunehmender Anzahl und Größe, bis diese vollkommen
zum Erliegen kommt. Seit mehreren Jahrzehnten werden Tiermodelle mit PKD für die Aufklärung der molekularen Mechanismen der
Zystogenese verwendet. War man anfangs auf zufällige, durch Spontanmutationen aufgetretene Zystenmodelle angewiesen, eröffneten
transgene und Knock-out-Technologien in den letzen 20 Jahren eine völlig neue Dimension, die molekularen Pathomechanismen
der Zystogenese durch gezielte genetische Veränderungen im Erbgut aufzuklären. Nur mit der Hilfe von Tiermodellen konnte die
Lokalisation von „Zystenproteinen“ in den Zilien und die Beteiligung zilienabhängiger Signalkaskaden in der Zystogenese gezeigt
werden. Dieser Artikel gibt einen Überblick über die derzeit vorhandenen murinen Tiermodelle mit PKD.
Polycystic kidney disease (PKD) is the most common genetic cause for end-stage renal failure. Numerous fluid-filled cysts
develop in the parenchyma of the kidney. They compromise kidney function with increasing number and size of the cysts until
renal failure is inevitable. The cysts are epithelial in origin but cysts develop in different nephron segments depending
on the type of the PKD. Animal models with PKD have been used for several decades to unravel the molecular mechanisms of cystogenesis.
Initially, research was dependent on the morphological analysis of spontaneously emerging cystic phenotypes. Nowadays, in
addition to theses models transgenic and knock-out models targeting PKD genes are also available. The localization of “cystoproteins”
in the cilia of the tubulus epithelia and the involvement of cilia-dependent pathways in cystogenesis was shown only with
the help of these animal models. This article gives an overview on the currently available murine models presenting with PKD.
KeywordsPolycystic kidney diseases-Models, animal-Cilia-Cystoproteins-Ciliopathy
Medizinische Genetik 09/2010; 22(3):332-338. DOI:10.1007/s11825-010-0230-3 · 0.13 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.