bims-bicyki 2022-06-19 papers

bims-bicyki

Biomed News

on Bicaudal-C1 and interactors in cystic kidney disease

Issue of 2022–06–19
eight papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne

Echocardiographic Findings and Genotypes in Autosomal Dominant Polycystic Kidney Disease.
A cAMP signalosome in primary cilia drives gene expression and kidney cyst formation.
Research priorities for autosomal dominant polycystic kidney disease: a UK priority setting partnership.
HaCaT cells as a model system to study primary cilia in keratinocytes.
Molecular basis underlying the ciliary defects caused by IFT52 variations found in skeletal ciliopathies.
Daw1 regulates the timely onset of cilia motility during development.
Ciliogenesis mechanisms mediated by PAK2-ARL13B signaling in brain endothelial cells is responsible for vascular stability.
Imaging of the Ciliary Body: A Major Review.

Kidney Dis (Basel). 2022 May;8(3): 246-252

Echocardiographic Findings and Genotypes in Autosomal Dominant Polycystic Kidney Disease.

Ryohei Miyamoto, Akinari Sekine, Takuya Fujimaru, Tatsuya Suwabe, Hiroki Mizuno, Eiko Hasegawa, Masayuki Yamanouchi, Motoko Chiga, Takayasu Mori, Eisei Sohara, Shinichi Uchida, Naoki Sawa, Yoshifumi Ubara, Junichi Hoshino.

   Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary cystic kidney disease and is well known to have extrarenal complications. Cardiovascular complications are of particular clinical relevance because of their morbidity and mortality; however, unclear is why they occur so frequently in patients with ADPKD and whether they are related to the genotypes.
Methods: We extracted and retrospectively analyzed clinical data on patients with ADPKD who underwent echocardiography and whose genotype was confirmed by genetic testing between April 2016 and December 2020. We used next-generation sequencing to compare cardiac function, structural data, and the presence of cardiac valvular disease in patients with 1 of 3 genotypes: PKD1, PKD2, and non-PKD1, 2.
Results: This retrospective study included 65 patients with ADPKD. Patients were divided into 3 groups: PKD1, n = 32; PKD2, n = 12; and non-PKD1, 2, n = 21. The prevalence of mitral regurgitation (MR) was significantly higher in the PKD1 group than in the PKD2 and non-PKD1, 2 group (46.9% vs. 8.3% vs. 19.0%, respectively; p = 0.02). In contrast, no significant difference was found for other cardiac valve complications.
Conclusion: This study found a significantly higher prevalence of MR in patients with the PKD1 genotype than in those with the PKD2 or non-PKD1, 2 genotypes. Physicians may need to perform echocardiography earlier and more frequently in patients with ADPKD and the PKD1 genotype and to control fluid volume and blood pressure more strictly in these patients to prevent future cardiac events.

Keywords:  Autosomal dominant polycystic kidney disease; Cardiovascular disease; Mitral regurgitation; PKD1; PKD2

DOI:  https://doi.org/10.1159/000520300
EMBO Rep. 2022 Jun 13. e54315

A cAMP signalosome in primary cilia drives gene expression and kidney cyst formation.

Jan N Hansen, Fabian Kaiser, Philipp Leyendecker, Birthe Stüven, Jens-Henning Krause, Fatemeh Derakhshandeh, Jaazba Irfan, Tommy J Sroka, Kenley M Preval, Paurav B Desai, Michael Kraut, Heidi Theis, Anna-Dorothee Drews, Elena De-Domenico, Kristian Händler, Gregory J Pazour, David J P Henderson, David U Mick, Dagmar Wachten.

  The primary cilium constitutes an organelle that orchestrates signal transduction independently from the cell body. Dysregulation of this intricate molecular architecture leads to severe human diseases, commonly referred to as ciliopathies. However, the molecular underpinnings how ciliary signaling orchestrates a specific cellular output remain elusive. By combining spatially resolved optogenetics with RNA sequencing and imaging, we reveal a novel cAMP signalosome that is functionally distinct from the cytoplasm. We identify the genes and pathways targeted by the ciliary cAMP signalosome and shed light on the underlying mechanisms and downstream signaling. We reveal that chronic stimulation of the ciliary cAMP signalosome transforms kidney epithelia from tubules into cysts. Counteracting this chronic cAMP elevation in the cilium by small molecules targeting activation of phosphodiesterase-4 long isoforms inhibits cyst growth. Thereby, we identify a novel concept of how the primary cilium controls cellular functions and maintains tissue integrity in a specific and spatially distinct manner and reveal novel molecular components that might be involved in the development of one of the most common genetic diseases, polycystic kidney disease.

Keywords:  CREB; PKD; cAMP; optogenetics; primary cilia

DOI:  https://doi.org/10.15252/embr.202154315
BMJ Open. 2022 Jun 15. 12(6): e055780

Research priorities for autosomal dominant polycystic kidney disease: a UK priority setting partnership.

Tess Harris, Hannah R Bridges, Wendy D Brown, Natasha L O'Brien, Ann C Daly, Bharat K Jindal, Gillian S Mundy, Albert Ong, Albert J Power, Richard N Sandford, John Sayer, Roslyn J Simms, Patricia D Wilson, Paul J D Winyard, Maryrose Tarpey.

   OBJECTIVES: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney condition, accounting for 7%-10% of patients with kidney failure. Fundamental basic science and clinical research on ADPKD is underway worldwide but no one has yet considered which areas should be prioritised to maximise returns from limited future funding. The Polycystic Kidney Disease Charity began a priority setting partnership with the James Lind Alliance (JLA) in the UK in 2019-2020 to identify areas of uncertainty in the ADPKD care pathway and allow patients, carers and healthcare professionals to rank the 10 most important questions for research.
DESIGN: The scope covered ADPKD diagnosis and management, identifying new treatments to prevent/slow disease progression and practical, integrated patient support (https://pkdcharity.org.uk/research/for-researchers/adpkd-research-priorities). We used adapted JLA methodology. Initially, an independent information specialist collated uncertainties in ADPKD care from recent consensus conference proceedings and additional literature. These were refined into indicative questions with Steering Group oversight. Finally, the 10 most important questions were established via a survey and online consensus workshop.
SETTING: UK.
PARTICIPANTS: 747 survey respondents (76% patients, 13% carers, 11% healthcare professionals); 23 workshop attendees.
RESULTS: 117 uncertainties in ADPKD care were identified and refined into 35 indicative questions. A shortlist of 17 questions was established through the survey. Workshop participants reached agreement on the top 10 ranking. The top three questions prioritised by patients, carers and healthcare professionals centred around slowing disease progression, identifying persons for early treatment and organising care to improve outcomes.
CONCLUSIONS: Our shortlist reflects the varied physical, psychological and practical challenges of living with and treating ADPKD, and perceived gaps in knowledge that impair optimal care. We propose that future ADPKD research funding takes these priorities into account to focus on the most important areas and to maximise improvements in ADPKD outcomes.

Keywords:  hepatology; nephrology; pain management

DOI:  https://doi.org/10.1136/bmjopen-2021-055780
Exp Dermatol. 2022 Jun 16.

HaCaT cells as a model system to study primary cilia in keratinocytes.

Gabriela Blanchard, Christine Pich, Daniel Hohl.

  Primary cilium (PC) is a microtubule-based organelle found on the apical surface of most mammalian cell types, playing a role in development and tissue homeostasis. Ciliopathies are a rapidly growing group of human diseases characterized by disordered cilium. PC plays an important a role in pathogenesis of basal cell cancer , the most common human malignancy. A significant increase in ciliation has been observed in the epidermis of atopic dermatitis and psoriasis patients. Spontaneously immortalized human keratinocytes, HaCaT are a model to study the epidermal homeostasis and pathophysiology. In contrast to what has been previously described, here, we show that HaCaT can be efficiently ciliated. In HaCaT cells, differentiation significantly increased the number of ciliated cells and we were able to analyze in detail the ciliary length progression with duration of differentiation. As the number of recognized ciliopathies continues to increase, the importance of ciliary models also rises. Even though keratinocytes do not become as highly and rapidly ciliated as cell lines frequently used in ciliary studies, they are a better model for the study of skin ciliopathies. Detailed progression of ciliation in HaCaT could serve as the basis for ciliary studies in this cell line.

Keywords:  cancer; differentiation; keratinocyte biology; keratinocytes; primary cilium

DOI:  https://doi.org/10.1111/exd.14626
Mol Biol Cell. 2022 Jun 15. mbcE22050188

Molecular basis underlying the ciliary defects caused by IFT52 variations found in skeletal ciliopathies.

Yamato Ishida, Koshi Tasaki, Yohei Katoh, Kazuhisa Nakayama.

Bidirectional protein trafficking within cilia is mediated by the intraflagellar transport (IFT) machinery, which contains the IFT-A and IFT-B complexes powered by the kinesin-2 and dynein-2 motors. Mutations in genes encoding subunits of the IFT-A and dynein-2 complexes cause skeletal ciliopathies. Some subunits of the IFT-B complex, including IFT52, IFT80, and IFT172, are also mutated in skeletal ciliopathies. We here show that IFT52 variants found in individuals with short-rib polydactyly syndrome (SRPS) are compromised in terms of formation of the IFT-B holocomplex from two subcomplexes, and its interaction with heterotrimeric kinesin-II. IFT52-knockout (KO) cells expressing IFT52 variants that mimic the cellular conditions of individuals with SRPS demonstrated mild ciliogenesis defects and a decrease in ciliary IFT-B level. Furthermore, in IFT52-KO cells expressing an SRPS variant of IFT52, ciliary tip localization of ICK/CILK1 and KIF17, both of which are likely to be transported to the tip via binding to the IFT-B complex, were significantly impaired. These results altogether indicate that impaired anterograde trafficking caused by a decrease in the ciliary level of IFT-B or in its binding to kinesin-II underlies the ciliary defects found in skeletal ciliopathies caused by IFT52 variations.

DOI: https://doi.org/10.1091/mbc.E22-05-0188
Development. 2022 Jun 15. pii: dev200017. [Epub ahead of print]149(12):

Daw1 regulates the timely onset of cilia motility during development.

Elizabeth A Bearce, Zoe H Irons, Samuel B Craig, Colin J Kuhns, Cynthia Sabazali, Dylan R Farnsworth, Adam C Miller, Daniel T Grimes.

  Motile cilia generate cell propulsion and extracellular fluid flows that are crucial for airway clearance, fertility and left-right patterning. Motility is powered by dynein arm complexes that are assembled in the cytoplasm then imported into the cilium. Studies in Chlamydomonas reinhardtii showed that ODA16 is a cofactor which promotes dynein arm import. Here, we demonstrate that the zebrafish homolog of ODA16, Daw1, facilitates the onset of robust cilia motility during development. Without Daw1, cilia showed markedly reduced motility during early development; however, motility subsequently increased to attain close to wild-type levels. Delayed motility onset led to differential effects on early and late cilia-dependent processes. Remarkably, abnormal body axis curves, which formed during the first day of development due to reduced cilia motility, self-corrected when motility later reached wild-type levels. Zebrafish larva therefore possess the ability to survey and correct body shape abnormalities. This work defines Daw1 as a factor which promotes the onset of timely cilia motility and can explain why human patients harboring DAW1 mutations exhibit significant laterality perturbations but mild airway and fertility complications.

Keywords:  Axis development; Daw1; Motile cilia; Primary ciliary dyskinesia; Scoliosis; Zebrafish

DOI:  https://doi.org/10.1242/dev.200017
Biochem Pharmacol. 2022 Jun 11. pii: S0006-2952(22)00237-4. [Epub ahead of print] 115143

Ciliogenesis mechanisms mediated by PAK2-ARL13B signaling in brain endothelial cells is responsible for vascular stability.

Karthikeyan Thirugnanam, Shubhangi Prabhudesai, Emma Van Why, Amy Pan, Ankan Gupta, Koji Foreman, Rahima Zennadi, Kevin R Rarick, Surya M Nauli, Sean P Palecek, Ramani Ramchandran.

  In the developing vasculature, cilia, microtubule-based organelles that project from the apical surface of endothelial cells (ECs), have been identified to function cell autonomously to promote vascular integrity and prevent hemorrhage. To date, the underlying mechanisms of endothelial cilia formation (ciliogenesis) are not fully understood. Understanding these mechanisms is likely to open new avenues for targeting EC-cilia to promote vascular stability. Here, we hypothesized that brain ECs ciliogenesis and the underlying mechanisms that control this process are critical for brain vascular stability. To investigate this hypothesis, we utilized multiple approaches including developmental zebrafish model system and primary cell culture systems. In the p21 activated kinase 2 (pak2a) zebrafish vascular stability mutant [redhead (rhd)] that shows cerebral hemorrhage, we observed significant decrease in cilia-inducing protein ADP Ribosylation Factor Like GTPase 13B (Arl13b), and a 4-fold decrease in cilia numbers. Overexpressing ARL13B-GFP fusion mRNA rescues the cilia numbers (1-2-fold) in brain vessels, and the cerebral hemorrhage phenotype. Further, this phenotypic rescue occurs at a critical time in development (24 h post fertilization), prior to initiation of blood flow to the brain vessels. Extensive biochemical mechanistic studies in primary human brain microvascular ECs implicate ligands platelet-derived growth factor-BB (PDGF-BB), and vascular endothelial growth factor-A (VEGF-A) trigger PAK2-ARL13B ciliogenesis and signal through cell surface VEGFR-2 receptor. Thus, collectively, we have implicated a critical brain ECs ciliogenesis signal that converges on PAK2-ARL13B proteins to promote vascular stability.

Keywords:  PDGF-BB; VEGF-A; brain; cilia; vascular integrity; vasculature

DOI:  https://doi.org/10.1016/j.bcp.2022.115143
Semin Ophthalmol. 2022 Jun 11. 1-13

Imaging of the Ciliary Body: A Major Review.

Gazella Bruce Warjri, Sirisha Senthil.

   PURPOSE: We conducted a systematic search of literature to understand the various methods of imaging of the ciliary body.
METHODS: PubMed, Science Direct, Cochrane Library and Google Scholar were searched comprehensively and systematically to find studies related to the various modalities of ciliary body imaging.
RESULTS: The various ciliary body parameters that have been described are Ciliary body thickness, Ciliary body length, ciliary muscle thickness, ciliary process length, ciliary muscle length, ciliary muscle anterior length, trabecular ciliary process distance and Iris ciliary process distance. The various angles which have been measured, which mostly have a significance in Primary angle closure glaucoma (PACG) are Iris ciliary angle, Trabecular ciliary angle, scleral ciliary process angle. Various authors have defined them in various ways with subtle differences. Plateau iris and PACG mechanisms, not forgetting malignant glaucoma are better understood with imaging of the ciliary body using the ultrasound biomicroscopy (UBM). The anterior segment optical coherence tomography (ASOCT) imaging of the ciliary body has been described albeit with its own disadvantages. A few other fields dependant on the importance of ciliary body imaging are intravitreal injections, pars plana vitrectomy, measurements for implantable collamer lens (ICL) and of utmost importance, the differentiating features of ciliary body masses.
CONCLUSION: The UBM is still preferred over the ASOCT for imaging of the ciliary body. A lot of lacunae of knowledge still exists and consensus has to be reached on defining all the parameters universally. Future studies will be able to shed more light on the role of the ciliary body in the many ocular disorders mentioned in this review.

Keywords:  Anterior segment optical coherence tomography; Ciliary body; Ciliary body glaucoma; Ultrasound biomicroscopy

DOI:  https://doi.org/10.1080/08820538.2022.2085515