Ciliary exclusion of Polycystin-2 promotes kidney cystogenesis in an autosomal dominant polycystic kidney disease model

Walker, Rebecca; Keynton, Jennifer; Grimes, Daniel T.; Sreekumar, Vrinda; Williams, Debbie; Esapa, Chris; Wu, Dongsheng; Knight, Martin M.; Norris, Dominic P.

doi:10.1038/s41467-019-12067-y

Cited by 48 publications

(46 citation statements)

References 67 publications

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“…PKD2 is the most likely candidate for such a channel. Although PKD2 is a nonselective cation channel present in both the ciliary membrane and ER, its presence in the ciliary membrane is essential for L-R asymmetry in mouse embryos ( 6 , 31 ) as well as for preventing polycystic kidney disease in kidney epithelial cells ( 32 ).…”

Section: Discussionmentioning

confidence: 99%

Role of Ca ²⁺ transients at the node of the mouse embryo in breaking of left-right symmetry

et al. 2020

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Immotile cilia sense extracellular signals such as fluid flow, but whether Ca2+ plays a role in flow sensing has been unclear. Here, we examined the role of ciliary Ca2+ in the flow sensing that initiates the breaking of left-right (L-R) symmetry in the mouse embryo. Intraciliary and cytoplasmic Ca2+ transients were detected in the crown cells at the node. These Ca2+ transients showed L-R asymmetry, which was lost in the absence of fluid flow or the PKD2 channel. Further characterization allowed classification of the Ca2+ transients into two types: cilium-derived, L-R-asymmetric transients (type 1) and cilium-independent transients without an L-R bias (type 2). Type 1 intraciliary transients occurred preferentially at the left posterior region of the node, where L-R symmetry breaking takes place. Suppression of intraciliary Ca2+ transients delayed L-R symmetry breaking. Our results implicate cilium-derived Ca2+ transients in crown cells in initiation of L-R symmetry breaking in the mouse embryo.

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Section: Discussionmentioning

confidence: 99%

Role of Ca ²⁺ transients at the node of the mouse embryo in breaking of left-right symmetry

et al. 2020

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“…Here, we show ciliary localization of PKD-2 positively correlates with its release in environmental EVs. Ciliary localization of polycystin-2 is essential for preventing cystogenesis in a mouse model 18 and loss of cilia prevents cystogenesis in a Pkd2 mutant mouse 36 . We propose that ability of a cilium to package and shed polycystin-2 in EVs may be an important physiological process in the kidney and that defects in this process may contribute to cystogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Autosomal dominant polycystic kidney disease gene product, polycystin-2, localizes to cilia and extracellular vesicles (EVs) throughout evolution. Loss of ciliary localization of polycystin-2 leads to cystogenesis in mouse model 18 . The relationship between polycystin-2 ciliary localization and EV biogenesis represents a knowledge gap in the field.…”

Section: Mainmentioning

confidence: 99%

Sensory cilia act as a specialized venue for regulated EV biogenesis and signaling

Wang

Silva

et al. 2021

Preprint

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Extracellular vesicles play major roles in intercellular signaling, yet fundamental aspects of their biology remain poorly understood. Ciliary EV shedding is evolutionary conserved. Here we use super resolution,real time imaging of fluorescent-protein tagged EV cargo combined with in vivo bioassays to study signaling EVs in C. elegans. We find that neuronal sensory cilia shed the TRP polycystin-2 channel PKD-2::GFP-carrying EVs from two distinct sites - the ciliary tip and the ciliary base. Ciliary tip shedding requires distal ciliary enrichment of PKD-2 by the myristoylated coiled-coil protein CIL-7. Kinesin-3 KLP-6 and intraflagellar transport (IFT) kinesin-2 motors are also required for ciliary tip EV shedding. Blocking ciliary tip shedding results in excessive EV shedding from the base. Finally, we demonstrate that C. elegans male ciliated neurons modulate EV cargo composition in response to sensory stimulation by hermaphrodite mating partners. Overall, our study indicates that the cilium and its trafficking machinery act as a specialized venue for regulated EV biogenesis and signaling.

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“…Whereas the function of PC2 as a Ca 2+ -permeable cation channel is well-established, there currently exists controversy over where PC2 exerts its intrinsic channel function. It is thought that due to the ER retention signal within its C-terminal tail, the majority of PC2 is located on the ER 5,88 , with the rest being localized to the primary cilia in association with PC1 89 or TRPV4 90 , where it exerts its anti-cystogenic function 91 . However, others have suggested that PC2 is also present and functions as a Ca 2+ channel on the plasma membrane 92,93 .…”

Section: Discussionmentioning

confidence: 99%

Polycystin 2 is increased in disease to protect against stress-induced cell death

Brill

Fischer

Walters

et al. 2020

Sci Rep

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Polycystin 2 (PC2 or TRPP1, formerly TRPP2) is a calcium-permeant Transient Receptor Potential (TRP) cation channel expressed primarily on the endoplasmic reticulum (ER) membrane and primary cilia of all cell and tissue types. Despite its ubiquitous expression throughout the body, studies of PC2 have focused primarily on its role in the kidney, as mutations in PC2 lead to the development of autosomal dominant polycystic kidney disease (ADPKD), a debilitating condition for which there is no cure. However, the endogenous role that PC2 plays in the regulation of general cellular homeostasis remains unclear. In this study, we measure how PC2 expression changes in different pathological states, determine that its abundance is increased under conditions of cellular stress in multiple tissues including human disease, and conclude that PC2-deficient cells have increased susceptibility to cell death induced by stress. Our results offer new insight into the normal function of PC2 as a ubiquitous stress-sensitive protein whose expression is up-regulated in response to cell stress to protect against pathological cell death in multiple diseases. Polycystin-2 (PC2 or TRPP1, formerly TRPP2) is a Transient Receptor Potential (TRP) channel most well-known for its associated pathology. When mutated, PC2 causes autosomal dominant polycystic kidney disease (ADPKD), a debilitating condition leading to bilateral renal cyst formation and eventual kidney failure 1. Located primarily on the endoplasmic reticulum (ER) and primary cilia of all cell and tissue types 2-5 , PC2 is a calcium (Ca 2+)-permeant cation channel whose expression level directly affects Ca 2+ release from the ER 5. As such, PC2 is thought to play a key role in regulating Ca 2+-regulated homeostasis and signaling pathways 6. This is supported by findings showing that polycystin-deficient cells exhibit dysregulated Ca 2+ mobilization and Ca 2+-regulated signaling pathways 5,7 , including pathologically increased cAMP levels 8,9 and changes in mitochondrial Ca 2+ uptake 10,11. The aberrant Ca 2+ signaling caused by loss of polycystins is therefore often pointed to as a central cause of enhanced apoptosis 12,13 , excess fluid secretion 14,15 , and metabolic abnormalities 10,11,16-18 seen in cystic kidney cells. Given the importance of PC2 in ADPKD development, most studies of PC2 have focused on its function in the kidney. However, the ubiquitous expression of PC2 in all cell types suggests that it is important in maintaining Ca 2+ homeostasis in tissues beyond the kidney. The tight regulation of intracellular Ca 2+ is necessary for many physiological functions, including protecting cells against outside stressors. Oxidative and ER stress responses require Ca 2+ influx from both the extracellular

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Ciliary exclusion of Polycystin-2 promotes kidney cystogenesis in an autosomal dominant polycystic kidney disease model

Cited by 48 publications

References 67 publications

Role of Ca ²⁺ transients at the node of the mouse embryo in breaking of left-right symmetry

Role of Ca ²⁺ transients at the node of the mouse embryo in breaking of left-right symmetry

Sensory cilia act as a specialized venue for regulated EV biogenesis and signaling

Polycystin 2 is increased in disease to protect against stress-induced cell death

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Ciliary exclusion of Polycystin-2 promotes kidney cystogenesis in an autosomal dominant polycystic kidney disease model

Cited by 48 publications

References 67 publications

Role of Ca 2+ transients at the node of the mouse embryo in breaking of left-right symmetry

Role of Ca 2+ transients at the node of the mouse embryo in breaking of left-right symmetry

Sensory cilia act as a specialized venue for regulated EV biogenesis and signaling

Polycystin 2 is increased in disease to protect against stress-induced cell death

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Product

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Role of Ca ²⁺ transients at the node of the mouse embryo in breaking of left-right symmetry

Role of Ca ²⁺ transients at the node of the mouse embryo in breaking of left-right symmetry