bims-bicyki 2022-04-03 papers

bims-bicyki

Biomed News

on Bicaudal-C1 and interactors in cystic kidney disease

Issue of 2022–04–03
seventeen papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne

Management of autosomal dominant polycystic kidney disease in the era of disease-modifying treatment options.
Successful Treatment of Giant Common and Proper Hepatic Artery Aneurysm Complicating Autosomal Dominant Polycystic Kidney Disease1.
Obesity, Weight Loss, Lifestyle Interventions, and Autosomal Dominant Polycystic Kidney Disease.
Kidney Stone Formation in a Novel Murine Model of Polycystic Kidney Disease.
Platelet-derived growth factor-AA promotes placental choriocarcinoma JAR cell proliferation via primary cilia.
Netrin-1 overexpression induces polycystic kidney disease - a novel mechanism contributing cystogenesis in ADPKD.
Paramecium, a Model to Study Ciliary Beating and Ciliogenesis: Insights From Cutting-Edge Approaches.
Long Residence Time at the Vasopressin V2 Receptor Translates into Superior Inhibitory Effects in Ex Vivo and In Vivo Models of Autosomal Dominant Polycystic Kidney Disease.
Ciliogenesis membrane dynamics and organization.
Primary cilia and their effects on immune cell functions and metabolism: a model.
Cilia-derived vesicles: An ancient route for intercellular communication.
Tumor Treating Fields Suppression of Ciliogenesis Enhances Temozolomide Toxicity.
Chlorogenic acid improves the intestinal barrier by relieving endoplasmic reticulum stress and inhibiting ROCK/MLCK signaling pathways.
PLK1 controls centriole distal appendage formation and centrobin removal via independent pathways.
[Effect of polycystin2 on differentiation and maturation of osteoblasts promoted by low-frequency pulsed electromagnetic fields].
Chronic airway disease in primary ciliary dyskinesia-spiced with geno-phenotype associations.
Centrosome maturation requires phosphorylation-mediated sequential domain interactions of SPD-5.

Kidney Res Clin Pract. 2022 Mar 29.

Management of autosomal dominant polycystic kidney disease in the era of disease-modifying treatment options.

Yeshwanter Radhakrishnan, Parikshit Duriseti, Fouad T Chebib.

  Autosomal dominant polycystic kidney disease (ADPKD) is the reported etiology in 10% of end-stage kidney disease (ESKD) patients and has an estimated prevalence of 12.5 million cases worldwide across all ethnicities. There have been major advancements over the last two decades in understanding the pathogenesis and development of disease-modifying treatment options for ADPKD, culminating in regulatory approval of tolvaptan for ADPKD patients at risk of rapid progression to kidney failure. This review highlights the genetic mutations associated with ADPKD, defines patients at risk of rapid progression to ESKD, and focuses on the management of ADPKD in the era of disease-modifying agents.

Keywords:  Autosomal dominant polycystic kidney; Biomarkers; Chronic kidney diseases; Prognosis; Tolvaptan

DOI:  https://doi.org/10.23876/j.krcp.21.309
Ann Vasc Surg. 2022 Mar 23. pii: S0890-5096(22)00141-8. [Epub ahead of print]

Successful Treatment of Giant Common and Proper Hepatic Artery Aneurysm Complicating Autosomal Dominant Polycystic Kidney Disease1.

Michihisa Umetsu, Daijirou Akamatsu, Hitoshi Goto, Munetaka Hashimoto, Fukashi Serizawa, Yuta Tajima, Shinichiro Horii, Norinobu Ogasawara, Hirokazu Takahashi, Yohei Nagaoka, Takashi Kamei.

  Hepatic artery aneurysms (HAAs) complicating autosomal dominant polycystic kidney disease (ADPKD) are extremely rare. Owing to the large number of renal cysts in ADPKD, ingenuity is required to safely perform surgery for HAA. Here, we present the case of a 60-year-old man with a common and proper HAA of >60 mm complicated with ADPKD. In this patient, difficulty in maintaining the field of view was expected during surgery. Hence, we performed a hybrid approach with celiac-to-right hepatic artery bypass by puncturing the femoral artery and cannulating the splenic artery to allow celiac-splenic artery balloon occlusion in case of rupture. More than 5 years postoperatively, the graft is patent without intervention.

Keywords:  Autosomal dominant polycystic kidney disease; Common and proper hepatic artery aneurysm; common hepatic artery aneurysm

DOI:  https://doi.org/10.1016/j.avsg.2022.03.011
Kidney Dial. 2022 Mar;2(1): 106-122

Obesity, Weight Loss, Lifestyle Interventions, and Autosomal Dominant Polycystic Kidney Disease.

Cortney Steele, Kristen Nowak.

  Obesity remains a growing public health concern in industrialized countries around the world. The prevalence of obesity has also continued to rise in those with chronic kidney disease. Epidemiological data suggests those with overweight and obesity, measured by body mass index, have an increased risk for rapid kidney disease progression. Autosomal dominant polycystic kidney disease causes growth and proliferation of kidney cysts resulting in a reduction in kidney function in the majority of adults. An accumulation of adipose tissue may further exacerbate the metabolic defects that have been associated with ADPKD by affecting various cell signaling pathways. Lifestyle interventions inducing weight loss might help delay disease progression by reducing adipose tissue and systematic inflammation. Further research is needed to determine the mechanistic influence of adipose tissue on disease progression.

Keywords:  adipose tissue; chronic kidney disease; weight loss

DOI:  https://doi.org/10.3390/kidneydial2010013
Am J Physiol Renal Physiol. 2022 Mar 28.

Kidney Stone Formation in a Novel Murine Model of Polycystic Kidney Disease.

Heather A L RIddle, Shiqin Zhang, Feng Qian, James C Williams, Jason R Stubbs, Peter Stanley N Rowe, Stephen C Parnell.

  Individuals with autosomal dominant polycystic kidney disease (ADPKD) have a higher incidence of stone formation than the general population. However, there are no cystic animal models known to develop stones. Cystic mice compound heterozygous for hypomorphic Pkd1V and Pkd1RC alleles develop cystic kidneys within a few weeks of birth but live beyond twenty weeks of age, allowing for the study of cystic comorbidities including stone formation. Cystic Pkd1V/RC mice were sacrificed at 3, 13, or 26 weeks of age and their kidneys analyzed by micro-computed tomography (µCT) for stone formation. Mice had occasional mineral aggregates that could be detected by µCT analysis at 3 weeks of age. At 13 or 26 weeks of age, numerous white masses were visible beneath the kidney surface. µCT analysis confirmed the masses to be large mineral stone deposits throughout the renal cortex, with mineral content increasing with age. Staining of histological sections with Alizarin Red and von Kossa suggested that the stone deposits were composed primarily of calcium and phosphate. Microdissection confirmed stones localized within cyst lumens. Analysis of individual stones by µCT and infrared spectroscopy confirmed apatite mineral composition. Urinalysis revealed elevated levels of phosphate and citrate at 3 weeks of age, and lower pH and elevated levels of calcium and citrate at 13 weeks of age, suggesting altered phosphate and calcium homeostasis as a potential cause of mineralization and renal stone formation. This is the first animal model exhibiting overt kidney stone formation in the context of cystic kidney disease.

Keywords:  ADPKD; kidney stones; nephrolithiasis; polycystic kidney disease; polycystin-1

DOI:  https://doi.org/10.1152/ajprenal.00165.2021
Taiwan J Obstet Gynecol. 2022 Mar;pii: S1028-4559(22)00018-3. [Epub ahead of print]61(2): 299-305

Platelet-derived growth factor-AA promotes placental choriocarcinoma JAR cell proliferation via primary cilia.

Shi-Yuan Sheu, Chia-Yih Wang, Hui-Ling Cheng, Pei-Yin Tsai.

   OBJECTIVE: During early pregnancy, the proliferation placental cells is crucial for proper implantation and formation of maternal-fetal circulation. Platelet-derived growth factor-AA (PDGF-AA) has been detected in placenta during early pregnancy; however, the role of PDGF-AA in placental cell growth has not been studied extensively. Primary cilium, a centrosome-based cellular protrusion, is an signaling hub for regulating development and differentiation. Importantly, the receptor of PDGF-AA (Pdgfr-α) is detected in the primary cilium and primary cilia-mediated PDGF-AA signaling regulates development and differentiation. Here we would like to investigate whether PDGF-AA regulates placental cell growth and whether primary cilia play roles in this process.
MATERIALS AND METHODS: Human placental choriocarcinoma JAR cells were treated with PDGF-AA followed by examining cell growth. Primary cilia and subcellular localization of Pdgfr-α were observed by immunofluorescence staining. Manipulation of primary cilia was performed by treating cells with roscovitine or by transfecting cells with siRNA against IFT88.
RESULTS: Here we showed that PDGF-AA induced JAR cell proliferation. In addition, JAR cells grew primary cilia where Pdgfr-α was detected. More importantly, pharmacological inhibition of primary cilia formation or depletion of cilia-related gene, IFT88, alleviated PDGF-AA induced JAR cell proliferation.
CONCLUSION: Thus, our study show that PDGF-AA facilitates human placental choriocarcinomaJARcell growth via primary cilia.

Keywords:  Cell growth; IFT88; PDGF-AA; Placenta; Primary cilia

DOI:  https://doi.org/10.1016/j.tjog.2022.02.018
Am J Pathol. 2022 Mar 28. pii: S0002-9440(22)00104-3. [Epub ahead of print]

Netrin-1 overexpression induces polycystic kidney disease - a novel mechanism contributing cystogenesis in ADPKD.

Riyaz Mohamed, Yang Liu, Andreas D Kistler, Peter C Harris, Muthusamy Thangaraju.

  Despite recent advances in understanding the pathogenesis of polycystic kidney disease (PKD), the underlying molecular mechanisms involved in cystogenesis are not fully understood. Here, we describe a novel pathway involved in cyst formation. Transgenic mice overexpressing netrin-1 in proximal tubular cells showed increased production and urinary excretion of netrin-1. Although no cysts were detectable immediately after birth, numerous small cysts were evident by the age of 4 weeks and disease was accelerated along with age. Surprisingly, cyst formation in the kidney was restricted to male mice, with 80% penetrance. However, ovariectomy induced kidney cyst growth in netrin-1 overexpressing female mice. Cyst development in male was associated with albuminuria and polyuria and increased cAMP excretion in netrin-1 transgenic mice. Netrin-1 overexpression significantly increased ERK and FAK phosphorylation and vimentin expression. Interestingly, p53 expression was increased but in an inactive form. Furthermore, netrin-1 expression was increased in cystic epithelia and urine of various rodent models of PKD. siRNA mediated suppression of netrin-1 significantly reduced cyst growth and improved kidney function in netrin-1 transgenic mice and in two genetic animal models of PKD. Together, our data demonstrated that netrin-1 upregulation induced cyst formation in ADPKD.

Keywords:  ADPKD; Netrin-1; cystic kidney; polycystic kidney disease; proliferation

DOI:  https://doi.org/10.1016/j.ajpath.2022.03.004
Front Cell Dev Biol. 2022 ;10 847908

Paramecium, a Model to Study Ciliary Beating and Ciliogenesis: Insights From Cutting-Edge Approaches.

K Bouhouche, M S Valentine, P Le Borgne, M Lemullois, J Yano, S Lodh, A Nabi, A M Tassin, J L Van Houten.

  Cilia are ubiquitous and highly conserved extensions that endow the cell with motility and sensory functions. They were present in the first eukaryotes and conserved throughout evolution (Carvalho-Santos et al., 2011). Paramecium has around 4,000 motile cilia on its surface arranged in longitudinal rows, beating in waves to ensure movement and feeding. As with cilia in other model organisms, direction and speed of Paramecium ciliary beating is under bioelectric control of ciliary ion channels. In multiciliated cells of metazoans as well as paramecia, the cilia become physically entrained to beat in metachronal waves. This ciliated organism, Paramecium, is an attractive model for multidisciplinary approaches to dissect the location, structure and function of ciliary ion channels and other proteins involved in ciliary beating. Swimming behavior also can be a read-out of the role of cilia in sensory signal transduction. A cilium emanates from a BB, structurally equivalent to the centriole anchored at the cell surface, and elongates an axoneme composed of microtubule doublets enclosed in a ciliary membrane contiguous with the plasma membrane. The connection between the BB and the axoneme constitutes the transition zone, which serves as a diffusion barrier between the intracellular space and the cilium, defining the ciliary compartment. Human pathologies affecting cilia structure or function, are called ciliopathies, which are caused by gene mutations. For that reason, the molecular mechanisms and structural aspects of cilia assembly and function are actively studied using a variety of model systems, ranging from unicellular organisms to metazoa. In this review, we will highlight the use of Paramecium as a model to decipher ciliary beating mechanisms as well as high resolution insights into BB structure and anchoring. We will show that study of cilia in Paramecium promotes our understanding of cilia formation and function. In addition, we demonstrate that Paramecium could be a useful tool to validate candidate genes for ciliopathies.

Keywords:  basal body; cilia; ciliary beating; cryo-tomography; ion channel; paramecium; transition zone

DOI:  https://doi.org/10.3389/fcell.2022.847908
J Med Chem. 2022 Apr 01.

Long Residence Time at the Vasopressin V2 Receptor Translates into Superior Inhibitory Effects in Ex Vivo and In Vivo Models of Autosomal Dominant Polycystic Kidney Disease.

Haoran Zhang, Wenzhong Yan, Yongzhan Sun, Haoxing Yuan, Limin Su, Xudong Cao, Peng Wang, Zhou Xu, Youhui Hu, Zhongjian Wang, Yinan Wang, Kequan Fu, Ying Sun, Yupeng Chen, Jianjun Cheng, Dong Guo.

Prevailing strategies directing early-phase drug discovery heavily rely on equilibrium-based metrics such as affinity, which overlooks the kinetic process of a drug molecule interacting with its target. Herein, we developed a number of vasopressin V2 receptor (V2R) antagonists with divergent binding affinities and kinetics for autosomal dominant polycystic kidney disease (ADPKD). Surprisingly, the residence time of the V2R antagonists, but not their affinity, was correlated with the efficacy in both ex vivo and in vivo models of ADPKD. We envision that the kinetics-directed drug candidate selection and development may have general applicability for ADPKD and other therapeutic areas as well.

DOI: https://doi.org/10.1021/acs.jmedchem.2c00011
Semin Cell Dev Biol. 2022 Mar 26. pii: S1084-9521(22)00094-5. [Epub ahead of print]

Ciliogenesis membrane dynamics and organization.

Huijie Zhao, Ziam Khan, Christopher J Westlake.

  Ciliogenesis is a complex multistep process used to describe assembly of cilia and flagella. These organelles play essential roles in motility and signaling on the surface of cells. Cilia are built at the distal ends of centrioles through the formation of an axoneme that is surrounded by the ciliary membrane. As is the case in the biogenesis of other cellular organelles, regulators of membrane trafficking play essential roles in ciliogenesis, albeit with a unique feature that membranes are organized around microtubule-based structures. Membrane association with the distal end of the centriole is a critical initiating step for ciliogenesis. Studies of this process in different cell types suggests that a singular mechanism may not be utilized to initiate cilium assembly. In this review, we focus on recent insights into cilium biogenesis and the roles membrane trafficking regulators play in described ciliogenesis mechanisms with relevance to human disease.

Keywords:  Autophagy; Ciliogenesis; Ciliopathy; Membrane trafficking; centriole; cilia

DOI:  https://doi.org/10.1016/j.semcdb.2022.03.021
Trends Immunol. 2022 Mar 28. pii: S1471-4906(22)00050-3. [Epub ahead of print]

Primary cilia and their effects on immune cell functions and metabolism: a model.

Ernesto Picon-Galindo, Eicke Latz, Dagmar Wachten.

Primary cilia are hair-like protrusions of the plasma membrane that function as cellular antennae and are present on most cells in the human body. Primary cilia dysfunction leads to severe diseases, commonly termed 'ciliopathies'. A significant symptom of certain ciliopathies is obesity, and current research aims to identify contributing mechanisms of obesity development in these patients. Western lifestyle-associated factors can trigger chronic inflammation, or metaflammation, which can also attribute to obesity-associated metabolic disorders. However, obese individuals can also be 'metabolically healthy', as discussed for a subset of patients with obesity and ciliopathy. Here, we propose that primary cilia signaling might modulate specific immune cell phenotypes, behaviors, and functions, which might impact inflammatory responses in the context of ciliopathies and beyond.

DOI: https://doi.org/10.1016/j.it.2022.03.001
Semin Cell Dev Biol. 2022 Mar 25. pii: S1084-9521(22)00081-7. [Epub ahead of print]

Cilia-derived vesicles: An ancient route for intercellular communication.

Raj Luxmi, Stephen M King.

  Extracellular vesicles (EVs) provide a mechanism for intercellular communication that transports complex signals in membrane delimited structures between cells, tissues and organisms. Cells secrete EVs of various subtypes defined by the pathway leading to release and by the pathological condition of the cell. Cilia are evolutionarily conserved organelles that can act as sensory structures surveilling the extracellular environment. Here we discuss the secretory functions of cilia and their biological implications. Studies in multiple species - from the nematode Caenorhabditis elegans and the chlorophyte alga Chlamydomonas reinhardtii to mammals - have revealed that cilia shed bioactive EVs (ciliary EVs or ectosomes) by outward budding of the ciliary membrane. The content of ciliary EVs is distinct from that of other vesicles released by cells. Peptides regulate numerous aspects of metazoan physiology and development through evolutionarily conserved mechanisms. Intriguingly, cilia-derived vesicles have recently been found to mediate peptidergic signaling. C. reinhardtii releases the peptide α-amidating enzyme (PAM), bioactive amidated products and components of the peptidergic signaling machinery in ciliary EVs in a developmentally regulated manner. Considering the origin of cilia in early eukaryotes, it is likely that release of peptidergic signals in ciliary EVs represents an alternative and ancient mode of regulated secretion that cells can utilize in the absence of dedicated secretory granules.

Keywords:  Amidation; Chlamydomonas; Cilia; Ectosome; Peptidergic Signaling

DOI:  https://doi.org/10.1016/j.semcdb.2022.03.014
Front Oncol. 2022 ;12 837589

Tumor Treating Fields Suppression of Ciliogenesis Enhances Temozolomide Toxicity.

Ping Shi, Jia Tian, Brittany S Ulm, Julianne C Mallinger, Habibeh Khoshbouei, Loic P Deleyrolle, Matthew R Sarkisian.

  Tumor Treating Fields (TTFields) are low-intensity, alternating intermediate-frequency (200 kHz) electrical fields that extend survival of glioblastoma patients receiving maintenance temozolomide (TMZ) chemotherapy. How TTFields exert efficacy on cancer over normal cells or interact with TMZ is unclear. Primary cilia are microtubule-based organelles triggered by extracellular ligands, mechanical and electrical field stimulation and are capable of promoting cancer growth and TMZ chemoresistance. We found in both low- and high-grade patient glioma cell lines that TTFields ablated cilia within 24 h. Halting TTFields treatment led to recovered frequencies of elongated cilia. Cilia on normal primary astrocytes, neurons, and multiciliated/ependymal cells were less affected by TTFields. The TTFields-mediated loss of glioma cilia was partially rescued by chloroquine pretreatment, suggesting the effect is in part due to autophagy activation. We also observed death of ciliated cells during TTFields by live imaging. Notably, TMZ and TTFields have opposing effects on glioma ciliogenesis. TMZ-induced stimulation of ciliogenesis in both adherent cells and gliomaspheres was blocked by TTFields. Surprisingly, the inhibitory effects of TTFields and TMZ on tumor cell recurrence are linked to the relative timing of TMZ exposure to TTFields and ARL13B+ cilia. Finally, TTFields disrupted cilia in patient tumors treated ex vivo. Our findings suggest that the efficacy of TTFields may depend on the degree of tumor ciliogenesis and relative timing of TMZ treatment.

Keywords:  ARL13B; brain tumor; chemotherapy; cilium; electrical fields; treatment order

DOI:  https://doi.org/10.3389/fonc.2022.837589
Food Funct. 2022 Mar 30.

Chlorogenic acid improves the intestinal barrier by relieving endoplasmic reticulum stress and inhibiting ROCK/MLCK signaling pathways.

Luqing Song, Tao Wu, Li Zhang, Jin Wan, Zheng Ruan.

Phenolic acids play an active role in protecting the intestinal barrier, the structural integrity and function of which are crucial for host health. In the present study, we aimed to identify phenolic compounds that protect the intestine and explore the underlying mechanisms. We performed an imaging-based, quantitative, high-content screening (using Caco-2 and LS174T incubated with lipopolysaccharide/palmitic acid, respectively) to identify phenolic acids that could improve the mucosal barrier. We found that chlorogenic acid (CGA), 5-caffeoylquinic acid, protocatechuic acid, and caffeic acid alleviated intestinal barrier disruption. Furthermore, CGA increased transepithelial electrical resistance (TEER) and decreased paracellular permeability. Mechanistically, CGA inhibited the activation of myosin light chain kinase (MLCK) and Rho-associated kinase 1 (ROCK1) signals, thereby downregulating the expression of the downstream molecules phosphorylated myosin phosphatase target subunit 1 (p-MYPT1), MLCK, and phosphorylated myosin light chain (p-MLC), and upregulating the expression of tight junction proteins. In addition, CGA alleviated endoplasmic reticulum (ER) stress by inhibiting the expression levels of ER markers [glucose-regulated protein78 (GRP78) and C/EBP homologous protein (CHOP)] and the nuclear translocation of activating transcription factor 6 (ATF6), thereby promoting the expression of mucin [mucin 2 (Muc2), mucin 5AC (MUC5AC)] and secretory factor trefoil factor family 3 (TFF3) proteins. In summary, we identified four substances that can stabilise intestinal homeostasis. Of these, CGA protects the intestinal barrier by inhibiting ROCK/MLCK signalling pathways and relieving ER stress. These findings highlight the importance of rapidly screening potential active ingredients that benefit the intestinal barrier and provide a theoretical basis for enteral nutrition.

DOI: https://doi.org/10.1039/d1fo02662c
J Cell Sci. 2022 Mar 28. pii: jcs.259120. [Epub ahead of print]

PLK1 controls centriole distal appendage formation and centrobin removal via independent pathways.

Morgan Le Roux-Bourdieu, Devashish Dwivedi, Daniela Harry, Patrick Meraldi.

  Centrioles are central structural elements of centrosomes and cilia. In human cells daughter centrioles are assembled adjacent to existing centrioles in S-phase and reach their full functionality with the formation of distal and subdistal appendages one-and-a-half cell cycle later, as they exit their second mitosis. Current models postulate that the centriolar protein centrobin acts as placeholder for distal appendage proteins that must be removed to complete distal appendage formation. Here, we investigated in non-transformed human epithelial RPE1 cells the mechanisms controlling centrobin removal and its effect on distal appendage formation. Our data are consistent with a speculative model in which centrobin is removed from older centrioles due to a higher affinity for the newly born daughter centrioles, under the control of the centrosomal kinase Plk1. This removal also depends on the presence of subdistal appendage proteins on the oldest centriole. Removing centrobin, however, is not required for the recruitment of distal appendage proteins, even though this process is equally dependent on Plk1. We conclude that Plk1 kinase regulates centrobin removal and distal appendage formation during centriole maturation via separate pathways.

Keywords:  Cell cycle; Centrobin; Centrosome; Mitosis; Polo-like kinase 1

DOI:  https://doi.org/10.1242/jcs.259120
Sheng Wu Gong Cheng Xue Bao. 2022 Mar 25. 38(3): 1159-1172

[Effect of polycystin2 on differentiation and maturation of osteoblasts promoted by low-frequency pulsed electromagnetic fields].

Yueying He, Mingjun Yang, Zhuo Chen, Peng Wei, Kun Qin, Gaoqian Xie, Keming Chen.

  It is known that low-frequency pulsed electromagnetic fields (PEMFs) can promote the differentiation and maturation of rat calvarial osteoblasts (ROBs) cultured in vitro. However, the mechanism that how ROBs perceive the physical signals of PEMFs and initiate osteogenic differentiation remains unknown. In this study, we investigated the relationship between the promotion of osteogenic differentiation of ROBs by 0.6 mT 50 Hz PEMFs and the presence of polycystin2 (PC2) located on the primary cilia on the surface of ROBs. First, immunofluorescence staining was used to study whether PC2 is located in the primary cilia of ROBs, and then the changes of PC2 protein expression in ROBs upon treatment with PEMFs for different time were detected by Western blotting. Subsequently, we detected the expression of PC2 protein by Western blotting and the effect of PEMFs on the activity of alkaline phosphatase (ALP), as well as the expression of Runx-2, Bmp-2, Col-1 and Osx proteins and genes related to bone formation after pretreating ROBs with amiloride HCl (AMI), a PC2 blocker. Moreover, we detected the expression of genes related to bone formation after inhibiting the expression of PC2 in ROBs using RNA interference. The results showed that PC2 was localized on the primary cilia of ROBs, and PEMFs treatment increased the expression of PC2 protein. When PC2 was blocked by AMI, PEMFs could no longer increase PC2 protein expression and ALP activity, and the promotion effect of PEMFs on osteogenic related protein and gene expression was also offset. After inhibiting the expression of PC2 using RNA interference, PEMFs can no longer increase the expression of genes related to bone formation. The results showed that PC2, located on the surface of primary cilia of osteoblasts, plays an indispensable role in perceiving and transmitting the physical signals from PEMFs, and the promotion of osteogenic differentiation of ROBs by PEMFs depends on the existence of PC2. This study may help to elucidate the mechanism underlying the promotion of bone formation and osteoporosis treatment in low-frequency PEMFs.

Keywords:  RNA interference; amiloride hydrochloride; low-frequency pulsed electromagnetic field; osteoblasts; polycystin2

DOI:  https://doi.org/10.13345/j.cjb.210356
Am J Med Genet C Semin Med Genet. 2022 Mar 29.

Chronic airway disease in primary ciliary dyskinesia-spiced with geno-phenotype associations.

Kim G Nielsen, Mathias G Holgersen, Suzanne Crowley, June K Marthin.

  Primary ciliary dyskinesia (PCD) can be defined as a multiorgan ciliopathy with a dominant element of chronic airway disease affecting the nose, sinuses, middle ear, and in particular, the lower airways. Although most patients with PCD are diagnosed during preschool years, it is obvious that the chronic lung disease starts its course already from birth. The many faces of the clinical picture change, as does lung function, structural lung damage, the burden of infection, and of treatment throughout life. A markedly severe neutrophil inflammation in the respiratory tract seems pervasive and is only to a minimal extent ameliorated by a treatment strategy, which is predominantly aimed at bacterial infections. An ever-increasing understanding of the different aspects, their interrelationships, and possible different age courses conditioned by the underlying genotype is the focus of much attention. The future is likely to offer personalized medicine in the form of mRNA therapy, but to that end, it is of utmost importance that all patients with PCD be carefully characterized and given a genetic diagnosis. In this narrative review, we have concentrated on lower airways and summarized the current understanding of the chronic airway disease in this motile ciliopathy. In addition, we highlight the challenges, gaps, and opportunities in PCD lung disease research.

Keywords:  Primary; airway disease; chronic; ciliary; dyskinesia

DOI:  https://doi.org/10.1002/ajmg.c.31967
J Cell Sci. 2022 Apr 01. pii: jcs.259025. [Epub ahead of print]

Centrosome maturation requires phosphorylation-mediated sequential domain interactions of SPD-5.

Momoe Nakajo, Hikaru Kano, Kenji Tsuyama, Nami Haruta, Asako Sugimoto.

  Centrosomes consist of two centrioles and surrounding pericentriolar material (PCM). PCM expands during mitosis in a process called centrosome maturation, in which PCM scaffold proteins play pivotal roles to recruit other centrosomal proteins. In C. elegans, the scaffold protein SPD-5 forms PCM scaffold in a PLK-1 phosphorylation-dependent manner. However, how phosphorylation of SPD-5 promotes PCM scaffold assembly is unclear. Here, we identified three functional domains of SPD-5 through in vivo domain analyses, and propose that sequential domain interactions of SPD-5 are required for mitotic PCM scaffold assembly. Firstly, SPD-5 is targeted to centrioles through direct interaction between its centriole localization (CL) domain and a centriolar protein PCMD-1. Then, intra- and intermolecular interaction between SPD-5 phospho-regulated multimerization (PReM) domain and the PReM association (PA) domain is enhanced by phosphorylation by PLK-1, which leads to PCM scaffold expansion. Our findings suggest that the sequential domain interactions of scaffold proteins mediated by Polo/PLK-1 phosphorylation is an evolutionarily conserved mechanism of PCM scaffold assembly.

Keywords:  C. elegans; Centrosome maturation; PCMD-1; PLK-1; Pericentriolar material; SPD-5

DOI:  https://doi.org/10.1242/jcs.259025