scholarly journals Polycystic Diseases in Visceral Organs

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Shakila Abdul-Majeed ◽  
Surya M. Nauli
Keyword(s):  
Mammalian Cells ◽  
Primary Cilia ◽  
Polycystic Ovarian Syndrome ◽  
Cyst Formation ◽  
Apical Surface ◽  
Polycystic Kidney ◽  
Pancreas Disease ◽  
Polycystic Liver ◽  
And Function ◽  
Ovarian Syndrome

Primary cilia are nonmotile, microtubule-based, antenna-like organelles projecting from the apical surface of most mammalian cells. Elegant studies have established the importance of ciliary structure and function in signal transduction and the sensory roles of cilia in maintaining healthy cellular state. In particular, dysfunctional cilia have been implicated in a large number of diseases mainly characterized by the presence of fluid-filled cysts in various organs. Aside from polycystic kidney disease (PKD), however, the roles of cilia in polycystic liver disease (PLD), polycystic pancreas disease (PPD), and polycystic ovarian syndrome (PCOS) are still very vague. In addition, although gender and sex hormones are known to regulate cyst formation, their roles in regulating physiological functions of cilia need to be further explored.

scholarly journals Adult Inactivation of the Recessive Polycystic Kidney Disease Gene Causes Polycystic Liver Disease

Kidney360 ◽  
2020 ◽  
Vol 1 (10) ◽  
pp. 1066-1074
Author(s):  
Whitney Besse ◽  
Charlotte Roosendaal ◽  
Luigi Tuccillo ◽  
Sounak Ghosh Roy ◽  
Anna-Rachel Gallagher ◽  
...  
Keyword(s):  
Liver Disease ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Disease Gene ◽  
Cyst Formation ◽  
Polycystic Liver Disease ◽  
Polycystic Kidney ◽  
Liver Cysts ◽  
Second Hit ◽  
Polycystic Liver

BackgroundA major difference between autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD) lies in the pattern of inheritance, and the resultant timing and focality of cyst formation. In both diseases, cysts form in the kidney and liver as a consequence of the cellular recessive genotype of the respective disease gene, but this occurs by germline inheritance in ARPKD and somatic second hit mutations to the one normal allele in ADPKD. The fibrocystic liver phenotype in ARPKD is attributed to abnormal ductal plate formation because of the absence of PKHD1 expression during embryogenesis and organ development. The finding of polycystic liver disease in a subset of adult PKHD1 heterozygous carriers raises the question of whether somatic second hit mutations in PKHD1 in adults may also result in bile duct-derived cyst formation.MethodsWe used an adult-inducible Pkhd1 mouse model to examine whether Pkhd1 has a functional role in maintaining bile duct homeostasis after normal liver development.ResultsInactivation of Pkhd1 beginning at 4 weeks of age resulted in a polycystic liver phenotype with minimal fibrosis at 17 weeks. Increased biliary epithelium, which lines these liver cysts, was most pronounced in female mice. We assessed genetic interaction of this phenotype with either reduced or increased copies of Pkd1, and found no significant effects on the Pkhd1 phenotype in the liver or kidney from altered Pkd1 expression.ConclusionsSomatic adult inactivation of Pkhd1 results in a polycystic liver phenotype. Pkhd1 is a required gene in adulthood for biliary structural homeostasis independent of Pkd1. This suggests that PKHD1 heterozygous carrier patients can develop liver cysts after somatic mutations in their normal copy of PKHD1.

scholarly journals Ciliary subcellular localization of TGR5 determines the cholangiocyte functional response to bile acid signaling

2013 ◽  
Vol 304 (11) ◽  
pp. G1013-G1024 ◽  
Author(s):  
Anatoliy I. Masyuk ◽  
Bing Q. Huang ◽  
Brynn N. Radtke ◽  
Gabriella B. Gajdos ◽  
Patrick L. Splinter ◽  
...  
Keyword(s):  
Bile Acid ◽  
Functional Response ◽  
Primary Cilia ◽  
Intracellular Camp ◽  
Ciliated Cells ◽  
Functional Responses ◽  
Polycystic Liver ◽  
A Cell ◽  
And Function ◽  
In Cells

TGR5, the G protein-coupled bile acid receptor that transmits bile acid signaling into a cell functional response via the intracellular cAMP signaling pathway, is expressed in human and rodent cholangiocytes. However, detailed information on the localization and function of cholangiocyte TGR5 is limited. We demonstrated that in human (H69 cells) and rat cholangiocytes, TGR5 is localized to multiple, diverse subcellular compartments, with its strongest expression on the apical plasma, ciliary, and nuclear membranes. To evaluate the relationship between ciliary TGR5 and the cholangiocyte functional response to bile acid signaling, we used a model of ciliated and nonciliated H69 cells and demonstrated that TGR5 agonists induce opposite changes in cAMP and ERK levels in cells with and without primary cilia. The cAMP level was increased in nonciliated cholangiocytes but decreased in ciliated cells. In contrast, ERK signaling was induced in ciliated cholangiocytes but suppressed in cells without cilia. TGR5 agonists inhibited proliferation of ciliated cholangiocytes but activated proliferation of nonciliated cells. The observed differential effects of TGR5 agonists were associated with the coupling of TGR5 to Gαi protein in ciliated cells and Gαs protein in nonciliated cholangiocytes. The functional responses of nonciliated and ciliated cholangiocytes to TGR5-mediated bile acid signaling may have important pathophysiological significance in cilia-related liver disorders (i.e., cholangiociliopathies), such as polycystic liver disease. In summary, TGR5 is expressed on diverse cholangiocyte compartments, including a primary cilium, and its ciliary localization determines the cholangiocyte functional response to bile acid signaling.

Mechanical properties of primary cilia regulate the response to fluid flow

2010 ◽  
Vol 298 (5) ◽  
pp. F1096-F1102 ◽  
Author(s):  
Susanna Rydholm ◽  
Gordon Zwartz ◽  
Jacob M. Kowalewski ◽  
Padideh Kamali-Zare ◽  
Thomas Frisk ◽  
...  
Keyword(s):  
Mechanical Properties ◽  
Fluid Flow ◽  
Calcium Signaling ◽  
Mammalian Cells ◽  
Primary Cilia ◽  
Cyst Formation ◽  
Calcium Signal ◽  
Autosomal Dominant Polycystic Kidney ◽  
Stress Buildup ◽  
Surrounding Membrane

The primary cilium is a ubiquitous organelle present on most mammalian cells. Malfunction of the organelle has been associated with various pathological disorders, many of which lead to cystic disorders in liver, pancreas, and kidney. Primary cilia have in kidney epithelial cells been observed to generate intracellular calcium in response to fluid flow, and disruption of proteins involved in this calcium signaling lead to autosomal dominant polycystic kidney disease, implying a direct connection between calcium signaling and cyst formation. It has also been shown that there is a significant lag between the onset of flow and initiation of the calcium signal. The present study focuses on the mechanics of cilium bending and the resulting calcium signal. Visualization of real-time cilium movements in response to different types of applied flow showed that the bending is fast compared with the initiation of calcium increase. Mathematical modeling of cilium and surrounding membrane was performed to deduce the relation between bending and membrane stress. The results showed a delay in stress buildup that was similar to the delay in calcium signal. Our results thus indicate that the delay in calcium response upon cilia bending is caused by mechanical properties of the cell membrane.

scholarly journals Polycystin-2 (TRPP2) Regulates Primary Cilium Length in LLC-PK1 Renal Epithelial Cells

2020 ◽  
Author(s):  
Paula L. Perez ◽  
Noelia Scarinci ◽  
Horacio F. Cantiello ◽  
María del Rocío Cantero
Keyword(s):  
Epithelial Cells ◽  
Gene Silencing ◽  
Primary Cilium ◽  
Primary Cilia ◽  
Cyst Formation ◽  
Channel Blockers ◽  
Wild Type ◽  
Polycystic Kidney ◽  
Renal Epithelial Cells ◽  
Autosomal Dominant Polycystic Kidney

AbstractPolycystin-2 (PC2, TRPP2) is a Ca2+ permeable non-selective cation channel whose dysfunction generates autosomal dominant polycystic kidney disease (ADPKD). PC2 is present in different cell locations, including the primary cilium of renal epithelial cells. Little is known, however, as to whether PC2 contributes to the structure of the primary cilium. Here, we explored the effect(s) of external Ca2+, PC2 channel blockers, and PKD2 gene silencing on the length of primary cilia in wild type LLC-PK1 renal epithelial cells. To identify primary cilia and measure their length, confluent cell monolayers were fixed and immuno-labeled with an anti-acetylated α-tubulin antibody. Although primary cilia length measurements did not follow a Normal distribution, data were normalized by Box-Cox transformation rendering statistical difference under all experimental conditions. Cells exposed to high external Ca2+ (6.2 mM) decreased a 13.5% (p < 0.001) primary cilia length as compared to controls (1.2 mM Ca2+). In contrast, the PC2 inhibitors amiloride (200 μM) and LiCl (10 mM), both increased primary ciliary length by 33.2% (p < 0.001), and 17.4% (p < 0.001), respectively. PKD2 gene silencing by siRNA also elicited a statistically significant, 10.3% (p < 0.001) increase in primary cilia length, as compared to their respective scrambled RNA transfected cells. The data indicate that maneuvers that either regulate PC2 function or gene expression, modify the length of primary cilia in renal epithelial cells. Proper regulation of PC2 function in the primary cilium may be essential in the onset of mechanisms that trigger cyst formation in ADPKD.Significance StatementPolycystin-2 (PC2, TRPP2) is a Ca2+ permeable non-selective cation channel causing the autosomal dominant polycystic kidney disease (ADPKD). The importance of intact cilia and of fully functional polycystins in the onset of ADPKD cyst formation, point to yet unknown signaling mechanisms occurring within this organelle. We determined that the extracellular Ca2+ concentration, PC2 channel blockers, and PKD2 gene silencing, all contribute to the length of primary cilia in wild type LLC-PK1 renal epithelial cells. The data indicate that proper regulation of PC2 function in the primary cilium may be essential in the onset of mechanisms that trigger cyst formation in ADPKD.

scholarly journals STAM and Hrs Down-Regulate Ciliary TRP Receptors

2007 ◽  
Vol 18 (9) ◽  
pp. 3277-3289 ◽  
Author(s):  
Jinghua Hu ◽  
Samuel G. Wittekind ◽  
Maureen M. Barr
Keyword(s):  
Growth Factor ◽  
Mammalian Cells ◽  
Primary Cilia ◽  
Membrane Receptors ◽  
Sensory Transduction ◽  
Kinase Substrate ◽  
C Elegans ◽  
Early Endosomes ◽  
Transient Receptor ◽  
And Function

Cilia are endowed with membrane receptors, channels, and signaling components whose localization and function must be tightly controlled. In primary cilia of mammalian kidney epithelia and sensory cilia of Caenorhabditis elegans neurons, polycystin-1 (PC1) and transient receptor polycystin-2 channel (TRPP2 or PC2), function together as a mechanosensory receptor-channel complex. Despite the importance of the polycystins in sensory transduction, the mechanisms that regulate polycystin activity and localization, or ciliary membrane receptors in general, remain poorly understood. We demonstrate that signal transduction adaptor molecule STAM-1A interacts with C. elegans LOV-1 (PC1), and that STAM functions with hepatocyte growth factor–regulated tyrosine kinase substrate (Hrs) on early endosomes to direct the LOV-1-PKD-2 complex for lysosomal degradation. In a stam-1 mutant, both LOV-1 and PKD-2 improperly accumulate at the ciliary base. Conversely, overexpression of STAM or Hrs promotes the removal of PKD-2 from cilia, culminating in sensory behavioral defects. These data reveal that the STAM-Hrs complex, which down-regulates ligand-activated growth factor receptors from the cell surface of yeast and mammalian cells, also regulates the localization and signaling of a ciliary PC1 receptor-TRPP2 complex.

scholarly journals Acute inhibition of heterotrimeric kinesin-2 function reveals mechanisms of intraflagellar transport in mammalian cilia

2018 ◽  
Author(s):  
Martin F. Engelke ◽  
Bridget Waas ◽  
Sarah E. Kearns ◽  
Ayana Suber ◽  
Allison Boss ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Primary Cilia ◽  
Intraflagellar Transport ◽  
Genetic Approach ◽  
Ciliated Cells ◽  
Loss Of Function ◽  
Double Knockout ◽  
Chemical Genetic ◽  
Species Specific ◽  
And Function

ABSTRACTThe trafficking of components within cilia, called intraflagellar transport (IFT), is powered by kinesin-2 and dynein-2 motors. Loss of function in any subunit of the heterotrimeric KIF3A/KIF3B/KAP kinesin-2 motor prevents ciliogenesis in mammalian cells and has hindered an understanding of how kinesin-2 motors function in IFT. We used a chemical-genetic approach to engineer an inhibitable KIF3A/KIF3B (i3A/i3B) kinesin-2 motor that is capable of rescuing WT motor function in Kif3a/Kif3b double-knockout cells. Inhibitor addition blocks ciliogenesis or, if added to ciliated cells, blocks IFT within two minutes, which leads to a complete loss of primary cilia within six hours. The kinesin-2 family members KIF3A/KIF3C and KIF17 cannot rescue ciliogenesis in Kif3a/Kif3b double-knockout cells nor delay the disassembly of full-formed cilia upon i3A/i3B inhibition. These data suggest that KIF3A/KIF3B/KAP is the sole and essential motor for cilia assembly and function in mammalian cells, indicating a species-specific adaptation of kinesin-2 motors for IFT function.

scholarly journals The WD40 protein Morg1 facilitates Par6–aPKC binding to Crb3 for apical identity in epithelial cells

2013 ◽  
Vol 200 (5) ◽  
pp. 635-650 ◽  
Author(s):  
Junya Hayase ◽  
Sachiko Kamakura ◽  
Yuko Iwakiri ◽  
Yoshihiro Yamaguchi ◽  
Tomoko Izaki ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Epithelial Cells ◽  
Tight Junction ◽  
Apical Membrane ◽  
Transmembrane Protein ◽  
Cyst Formation ◽  
Cell Polarization ◽  
Small Gtpase ◽  
Apical Surface ◽  
And Function

Formation of apico-basal polarity in epithelial cells is crucial for both morphogenesis (e.g., cyst formation) and function (e.g., tight junction development). Atypical protein kinase C (aPKC), complexed with Par6, is considered to translocate to the apical membrane and function in epithelial cell polarization. However, the mechanism for translocation of the Par6–aPKC complex has remained largely unknown. Here, we show that the WD40 protein Morg1 (mitogen-activated protein kinase organizer 1) directly binds to Par6 and thus facilitates apical targeting of Par6–aPKC in Madin-Darby canine kidney epithelial cells. Morg1 also interacts with the apical transmembrane protein Crumbs3 to promote Par6–aPKC binding to Crumbs3, which is reinforced with the apically localized small GTPase Cdc42. Depletion of Morg1 disrupted both tight junction development in monolayer culture and cyst formation in three-dimensional culture; apico-basal polarity was notably restored by forced targeting of aPKC to the apical surface. Thus, Par6–aPKC recruitment to the premature apical membrane appears to be required for definition of apical identity of epithelial cells.

Experimental polycystic ovarian syndrome is associated with reduced expression and function of P2Y2 receptors in rat theca cells

2019 ◽  
Vol 86 (3) ◽  
pp. 308-318
Author(s):  
Anaí del Rocío Campos-Contreras ◽  
Ana Patricia Juárez-Mercado ◽  
Adriana González-Gallardo ◽  
Rebeca Chávez-Genaro ◽  
Edith Garay ◽  
...  
Keyword(s):  
Polycystic Ovarian Syndrome ◽  
P2y2 Receptors ◽  
Theca Cells ◽  
And Function ◽  
Ovarian Syndrome

scholarly journals Transient accumulation and bidirectional movement of KIF13B in primary cilia

2021 ◽  
Author(s):  
Alice Dupont Juhl ◽  
Zeinab Anvarian ◽  
Julia Berges ◽  
Daniel Wustner ◽  
Lotte B Pedersen
Keyword(s):  
Mammalian Cells ◽  
Live Cell Imaging ◽  
Primary Cilia ◽  
Cell Imaging ◽  
Intraflagellar Transport ◽  
Cytoplasmic Dynein ◽  
Ciliary Membrane ◽  
Bidirectional Movement ◽  
And Function ◽  
Male Specific

Primary cilia are microtubule-based sensory organelles whose assembly and function rely on the conserved bidirectional intraflagellar transport (IFT) system, which is powered by anterograde kinesin-2 and retrograde cytoplasmic dynein 2 motors. Nematodes additionally employ a male-specific kinesin-3 motor, KLP-6, which regulates ciliary content and function by promoting release of bioactive extracellular vesicles (EVs) from cilia. Here we show by live cell imaging that a KLP-6 homolog, KIF13B, undergoes bursts of bidirectional movement within primary cilia of cultured mammalian cells at 0.64 +/- 0.07 μm/s in the anterograde direction and at 0.39 +/- 0.06 μm/s in the retrograde direction, reminiscent of conventional IFT. In addition, we found that KIF13B undergoes EV-like release from the ciliary tip whereas a ciliary membrane marker, SMO-tRFP, remains stably associated with cilia during such EV release. Our results suggest that KIF13B, similar to KLP-6, regulates ciliary membrane content by promoting ciliary EV release, possibly in coordination with conventional IFT.

Sign in / Sign up

Export Citation Format

Share Document