bims-bicyki 2021-09-12 papers

bims-bicyki

Biomed News

on Bicaudal-C1 and interactors in cystic kidney disease

Issue of 2021–09–12
nineteen papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne

Autosomal recessive polycystic kidney disease.
Pre-clinical evaluation of dual targeting of the GPCRs CaSR and V2R as therapeutic strategy for autosomal dominant polycystic kidney disease.
Differential Diagnosis and Prognosis of Fetuses with Bilateral Enlarged, Hyperechogenic Kidneys: Renal Volume and Amniotic Fluid Volume with Advancing Gestation.
Cilia, Centrosomes and Skeletal Muscle.
[Clinical feature and genetic analysis of a fetus with autosomal recessive polycystic kidney disease].
Polycystin-1 dependent regulation of polycystin-2 via GRP94, a member of HSP90 family that resides in the endoplasmic reticulum.
Ciliary GPCR-based transcriptome as a key regulator of cilia length control.
The dynamic organelle primary cilia: emerging roles in organ fibrosis.
The Primary Cilium on Cells of Developing Skeletal Rudiments; Distribution, Characteristics and Response to Mechanical Stimulation.
Primary Cilia Enhance Osteogenic Response of Jaw Mesenchymal Stem Cells to Hypoxia and Bisphosphonate.
Control of the Hedgehog pathway by compartmentalized PKA in the primary cilium.
2-IPMA Ameliorates PM2.5-Induced Inflammation by Promoting Primary Ciliogenesis in RPE Cells.
Prenatal alcohol exposure disrupts Sonic hedgehog pathway and primary cilia genes in the mouse neural tube.
A Close Look at the Clinical Efficacy of Rho-Associated Protein Kinase Inhibitor Eye Drops for Fuchs Endothelial Corneal Dystrophy.
Molecular mechanisms underlying the role of the centriolar CEP164-TTBK2 complex in ciliopathies.
Cilium induction triggers differentiation of glioma stem cells.
Loss of Ift74 Leads to Slow Photoreceptor Degeneration and Ciliogenesis Defects in Zebrafish.
Targeting the Wnt/β-Catenin Signaling Pathway as a Potential Therapeutic Strategy in Renal Tubulointerstitial Fibrosis.
Renal and Extra Renal Manifestations in Adult Zebrafish Model of Cystinosis.

Am J Obstet Gynecol. 2021 Sep 07. pii: S0002-9378(21)00671-2. [Epub ahead of print]

Autosomal recessive polycystic kidney disease.

Society for Maternal-Fetal Medicine (SMFM)

DOI: https://doi.org/10.1016/j.ajog.2021.06.038
FASEB J. 2021 Oct;35(10): e21874

Pre-clinical evaluation of dual targeting of the GPCRs CaSR and V2R as therapeutic strategy for autosomal dominant polycystic kidney disease.

Annarita Di Mise, Xiaofang Wang, Hong Ye, Lorenzo Pellegrini, Vicente E Torres, Giovanna Valenti.

  Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations of PKD1 or PKD2 genes, is characterized by development and growth of cysts causing progressive kidney enlargement. Reduced resting cytosolic calcium and increased cAMP levels associated with the tonic action of vasopressin are two central biochemical defects in ADPKD. Here we show that co-targeting two GPCRs, the vasopressin V2 receptor (V2R) and the calcium sensing receptor, using the novel V2R antagonist lixivaptan in combination with the calcimimetic R-568, reduced cyst progression in two animal models of human PKD. Lixivaptan is expected to have a safer liver profile compared to tolvaptan, the only drug approved to delay PKD progression, based on computational model results and initial clinical evidence. PCK rat and Pkd1RC/RC mouse littermates were fed without or with lixivaptan (0.5%) and R-568 (0.025% for rats and 0.04% for mice), alone or in combination, for 7 (rats) or 13 (mice) weeks. In PCK rats, the combined treatment strongly decreased kidney weight, cyst and fibrosis volumes by 20%, 49%, and 73%, respectively, compared to untreated animals. In Pkd1RC/RC mice, the same parameters were reduced by 20%, 56%, and 69%, respectively. In both cases the combined treatment appeared nominally more effective than the individual drugs used alone. These data point to an intriguing new application for two existing drugs in PKD treatment. The potential for synergy between these two compounds suggested in these animal studies, if confirmed in appropriate clinical investigations, would represent a welcome advancement in the treatment of ADPKD.

Keywords:  GPCRs; calcimimetics; calcium-sensing receptor; polycystic kidney disease; vaptans; vasopressin V2 receptor

DOI:  https://doi.org/10.1096/fj.202100774R
Z Geburtshilfe Neonatol. 2021 Sep 07.

Differential Diagnosis and Prognosis of Fetuses with Bilateral Enlarged, Hyperechogenic Kidneys: Renal Volume and Amniotic Fluid Volume with Advancing Gestation.

Ann-Katrin Morr, Beatrice Mosimann, Sibylle Tschumi, Daniel Surbek, Luigi Raio.

INTRODUCTION: This study's objective was to identify prenatal criteria helping differential diagnosis of bilateral enlarged, hyperechogenic kidneys, especially looking at development of renal volume and amniotic fluid volume with increasing gestational age.
METHOD: Retrospective analysis (single-center database) of all bilateral enlarged, hyperechogenic kidneys between 2000-2018. Renal enlargement was defined as renal volume>90th percentile. Evaluation included development of renal and amniotic fluid volume during pregnancy and fetal outcome.
RESULTS: 23 cases fulfilled the inclusion criteria. 12 pregnancies were terminated. For 11 continued pregnancies, longitudinal information on amniotic fluid volume and renal volume were available. 4 cases with oligohydramnios showed a progressive reduction; 6 cases with normal/increased amniotic fluid volume remained stable; in 1 case amniotic fluid volume normalized from initially being oligohydramnios. Regarding renal volume, 4 cases showed exponential enlargement, 3 cases linear progression; in 2 cases renal volume stabilized after initial progression; 2 cases showed initial progression and secondary regression. 4 fetuses survived: 3 autosomal dominant polycystic kidney diseases, 1 Bardet-Biedl syndrome.
CONCLUSION: Progressive reduction of amniotic fluid volume with exponential increase of renal volume is highly suggestive for autosomal recessive polycystic kidney disease. Cases of autosomal dominant polycystic kidney disease show a linear progression of renal volume>90th percentile and mostly normal amniotic fluid volume.

DOI: https://doi.org/10.1055/a-1586-5493
Int J Mol Sci. 2021 Sep 04. pii: 9605. [Epub ahead of print]22(17):

Cilia, Centrosomes and Skeletal Muscle.

Dominic C H Ng, Uda Y Ho, Miranda D Grounds.

  Primary cilia are non-motile, cell cycle-associated organelles that can be found on most vertebrate cell types. Comprised of microtubule bundles organised into an axoneme and anchored by a mature centriole or basal body, primary cilia are dynamic signalling platforms that are intimately involved in cellular responses to their extracellular milieu. Defects in ciliogenesis or dysfunction in cilia signalling underlie a host of developmental disorders collectively referred to as ciliopathies, reinforcing important roles for cilia in human health. Whilst primary cilia have long been recognised to be present in striated muscle, their role in muscle is not well understood. However, recent studies indicate important contributions, particularly in skeletal muscle, that have to date remained underappreciated. Here, we explore recent revelations that the sensory and signalling functions of cilia on muscle progenitors regulate cell cycle progression, trigger differentiation and maintain a commitment to myogenesis. Cilia disassembly is initiated during myoblast fusion. However, the remnants of primary cilia persist in multi-nucleated myotubes, and we discuss their potential role in late-stage differentiation and myofiber formation. Reciprocal interactions between cilia and the extracellular matrix (ECM) microenvironment described for other tissues may also inform on parallel interactions in skeletal muscle. We also discuss emerging evidence that cilia on fibroblasts/fibro-adipogenic progenitors and myofibroblasts may influence cell fate in both a cell autonomous and non-autonomous manner with critical consequences for skeletal muscle ageing and repair in response to injury and disease. This review addresses the enigmatic but emerging role of primary cilia in satellite cells in myoblasts and myofibers during myogenesis, as well as the wider tissue microenvironment required for skeletal muscle formation and homeostasis.

Keywords:  cytoskeleton; differentiation; extracellular matrix; myogenesis; primary cilia; proliferation; satellite cells

DOI:  https://doi.org/10.3390/ijms22179605
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2021 Sep 10. 38(9): 880-883

[Clinical feature and genetic analysis of a fetus with autosomal recessive polycystic kidney disease].

Shu Xyu, Chen Xyu, Yuan Lyu, Chuang Li, Caixia Liu.

OBJECTIVE: To explore the genetic etiology of a fetus with autosomal recessive polycystic kidney disease (ARPKD).
METHODS: Prenatal ultrasonography has revealed oligohydramnios and abnormal structure of fetal kidneys. After careful counseling, the couple opted induced abortion. With informed consent, genomic DNA was extracted from the muscle sample of the abortus and peripheral blood samples of the couple. High throughput whole exome sequencing was carried out to detect potential variants in relation with the disease. Suspected variants were verified by Sanger sequencing.
RESULTS: Prenatal ultrasound revealed increased size of fetal kidneys, with multiple hyperechos from the right kidney, and multiple hyperechos with anechoic masses within the left kidney. DNA sequencing revealed that the fetus has carried heterozygous variants of the PKHD1 gene, including c.7994T>C inherited from its father, and two heterozygous variants of the PKHD1 gene c.5681G>A from its mother.
CONCLUSION: The compound heterozygous c.7994T>C and c.5681G>A variants of the PKHD1 gene probably underlay the pathogenesis of ARPKD in this fetus. Above results can provide guidance for subsequent pregnancies of the couple.

DOI: https://doi.org/10.3760/cma.j.cn511374-20200617-00447
FASEB J. 2021 Oct;35(10): e21865

Polycystin-1 dependent regulation of polycystin-2 via GRP94, a member of HSP90 family that resides in the endoplasmic reticulum.

Qin Yao, Patricia Outeda, Hangxue Xu, Rebecca Walker, Denis Basquin, Feng Qian, Liudmila Cebotaru, Terry Watnick, Valeriu Cebotaru.

  Autosomal dominant polycystic kidney disease is a common inherited renal disorder that results from mutations in either PKD1 or PKD2, encoding polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Downregulation or overexpression of PKD1 or PKD2 in mouse models results in renal cyst formation, suggesting that the quantity of PC1 and PC2 needs to be maintained within a tight functional window to prevent cystogenesis. Here we show that enhanced PC2 expression is a common feature of PKD1 mutant tissues, in part due to an increase in Pkd2 mRNA. However, our data also suggest that more effective protein folding contributes to the augmented levels of PC2. We demonstrate that the unfolded protein response is activated in Pkd1 knockout kidneys and in Pkd1 mutant cells and that this is coupled with increased levels of GRP94, an endoplasmic reticulum protein that is a member of the HSP90 family of chaperones. GRP94 was found to physically interact with PC2 and depletion or chemical inhibition of GRP94 led to a decrease in PC2, suggesting that GRP94 serves as its chaperone. Moreover, GRP94 is acetylated and binds to histone deacetylase 6 (HDAC6), a known deacetylase and activator of HSP90 proteins. Inhibition of HDAC6 decreased PC2 suggesting that HDAC6 and GRP94 work together to regulate PC2 levels. Lastly, we showed that inhibition of GRP94 prevents cAMP-induced cyst formation in vitro. Taken together our data uncovered a novel HDAC6-GRP94-related axis that likely participates in maintaining elevated PC2 levels in Pkd1 mutant cells.

Keywords:  ADPKD; GRP94; HDAC6; HSP; HSP90; UPR; autophagy; chaperone; kidney; polycystin-1; polycystin-2; proteasome

DOI:  https://doi.org/10.1096/fj.202100325RR
FASEB Bioadv. 2021 Sep;3(9): 744-767

Ciliary GPCR-based transcriptome as a key regulator of cilia length control.

Yuki Kobayashi, Sakura Tomoshige, Kosuke Imakado, Yuko Sekino, Noriko Koganezawa, Tomoaki Shirao, Giovanne B Diniz, Tatsuo Miyamoto, Yumiko Saito.

  The primary cilium is a plasma membrane-protruding sensory organelle that efficiently conveys signaling cascades in a highly ordered microenvironment. Its signaling is mediated, in part, by a limited set of GPCRs preferentially enriched in the cilium membrane. This includes melanin-concentrating hormone (MCH) receptor 1 (MCHR1), which plays a role in feeding and mood. In addition to its receptor composition, the length of the cilium is a characteristic parameter that is implicated in its function. We previously found that MCH can dynamically shorten cilia length via the Gi/o and Akt pathways in both MCHR1-expressing hTERT-RPE1 cells (hRPE1 cells) and rat hippocampal neurons. However, the detailed mechanisms by which MCH regulates cilia length through ciliary MCHR1 remains unclear. In this study, we aimed to determine the transcriptome changes in MCHR1-expressing hRPE1 cells in response to MCH to identify the target molecules involved in cilia length regulation via MCHR1 activation. RNA sequencing analysis of ciliated cells subjected to MCH treatment showed upregulation of 424 genes and downregulation of 112 genes compared with static control cells. Validation by quantitative real-time PCR, knocking down, and CRISPR/Cas9-mediated knockout technology identified a molecule, PDZ and LIM domain-containing protein 5 (PDLIM5). Thus, it was considered as the most significant key factor for MCHR1-mediated shortening of cilia length. Additional analyses revealed that the actin-binding protein alpha-actinin 1/4 is a crucial downstream target of the PDLIM5 signaling pathway that exerts an effect on MCHR1-induced cilia shortening. In the endogenous MCHR1-expressing hippocampus, transcriptional upregulation of PDLIM5 and actinin 1/4, following the application of MCH, was detected when the MCHR1-positive cilia were shortened. Together, our transcriptome study based on ciliary MCHR1 function uncovered a novel and important regulatory step underlying cilia length control. These results will potentially serve as a basis for understanding the mechanism underlying the development of obesity and mood disorders.

Keywords:  G protein‐coupled receptor; PDLIM5; melanin‐concentrating hormone; primary cilia; transcriptome

DOI:  https://doi.org/10.1096/fba.2021-00029
Curr Opin Rheumatol. 2021 Sep 07.

The dynamic organelle primary cilia: emerging roles in organ fibrosis.

Dibyendu Bhattacharyya, Maria E Teves, John Varga.

PURPOSE OF REVIEW: Primary cilia, the antenna-like organelles on most mammalian cells, host key components of multiple morphogen signal transduction pathways. Mutations in genes responsible for primary cilia assembly and function generally result in pathological conditions known as ciliopathies, which underlie several diseases, including various forms of fibrosis. Primary cilia modulate cellular responses to extracellular cues, including TGF-β and morphogens, such as Hedgehog. Aberrant morphogen signaling is recognized as essential for the transition of mesenchymal progenitor cells to myofibroblasts, the key step in fibrosis. This article aims to provide a critical overview of recent developments and insights in primary cilia biology relevant to fibrosis.
RECENT FINDINGS: Several studies have highlighted the association of altered primary cilia with various forms of fibrosis. In a rather complex manner, the presence of primary cilia seems to be required for initiation of myofibroblast transition, whereas its loss promotes myofibroblast transition at a later stage. Recent evidence also suggested that noncanonical functions of ciliary transport proteins may influence, such cellular transitions independently of primary cilia. The possibility of opposing signaling regulations being topologically separated between primary cilia and plasma membrane could also be critical for fibrosis.
SUMMARY: Recent progress in the field suggests that primary cilia are critical mediators of the pathogenesis of fibrosis. Understanding the potential role of primary cilia in fibrosis and the underlying mechanisms may pave the way for entirely new approaches for fibrosis prevention and treatment of SSc.

DOI: https://doi.org/10.1097/BOR.0000000000000841
Front Cell Dev Biol. 2021 ;9 725018

The Primary Cilium on Cells of Developing Skeletal Rudiments; Distribution, Characteristics and Response to Mechanical Stimulation.

Claire A Shea, Paula Murphy.

  Embryo movement is important for tissue differentiation and the formation of functional skeletal elements during embryonic development: reduced mechanical stimulation results in fused joints and misshapen skeletal rudiments with concomitant changes in the signaling environment and gene expression profiles in both mouse and chick immobile embryos. Despite the clear relationship between movement and skeletogenesis, the precise mechanisms by which mechanical stimuli influence gene regulatory processes are not clear. The primary cilium enables cells to sense mechanical stimuli in the cellular environment, playing a crucial mechanosensory role during kidney development and in articular cartilage and bone but little is known about cilia on developing skeletal tissues. Here, we examine the occurrence, length, position, and orientation of primary cilia across developing skeletal rudiments in mouse embryos during a period of pronounced mechanosensitivity and we report differences and similarities between wildtype and muscle-less mutant (Pax3 Spd/Spd ) rudiments. Strikingly, joint regions tend to have cilia positioned and oriented away from the joint, while there was a less obvious, but still significant, preferred position on the posterior aspect of cells within the proliferative and hypertrophic zones. Regions of the developing rudiments have characteristic proportions of ciliated cells, with more cilia in the resting and joint zones. Comparing wildtype to muscle-less mutant embryos, cilia are shorter in the mutant with no significant difference in the proportion of ciliated cells. Cilia at the mutant joint were also oriented away from the joint line.

Keywords:  chondrogenesis; mechanical regulation; mechanosensory; morphogenesis; primary cilia; skeletal development; skeletogenesis

DOI:  https://doi.org/10.3389/fcell.2021.725018
J Oral Maxillofac Surg. 2021 Aug 05. pii: S0278-2391(21)00749-7. [Epub ahead of print]

Primary Cilia Enhance Osteogenic Response of Jaw Mesenchymal Stem Cells to Hypoxia and Bisphosphonate.

Yufan Wang, Sunday O Akintoye.

PURPOSE: Primary cilia play a significant role in mesenchymal stem cell (MSC) lineage commitment, skeletal development, and bone homeostasis. MSC responsiveness to metabolic stress is associated with radiation and drug-induced jaw osteonecrosis. Therefore, we hypothesize that orofacial MSCs (OFMSCs) osteogenic commitment in response to cellular stressors hypoxia and bisphosphonates is a survival response coupled to primary cilia biogenesis.
MATERIALS AND METHODS: Human OFMSCs were subjected to cellular stress using severe hypoxia, nitrogen-containing bisphosphonate (pamidronate) and low serum starvation. OFMSC primary cilia formation, as well as cell survival and proliferation, were detected using immunofluorescence, CellTitre-Glo, and WST-1 assays respectively. OFMSC differentiation was tested using Alizarin Red S staining. OFMSCs survival and osteogenic markers were assessed by western blotting relative to primary cilia number and associated acetylated tubulin levels.
RESULTS: Baseline OFMSC proliferation was stable under short-term severe hypoxia and pamidronate treatments whether combined with or without serum starvation. Hypoxia and pamidronate decreased the number of OFMSCs positive for primary cilia that was consistent with increased HIF-1α and caspase 3 but decreased cyclin D1. Combined effects of hypoxia and pamidronate on OFMSCs significantly reduced ciliation but did not completely abrogate it. Combination of serum deprivation, hypoxia, and pamidronate promoted OFMSCs osteogenic differentiation that was consistent with upregulated HIF-1α levels.
CONCLUSIONS: Partial rather than complete loss of OFMSC ciliation and enhanced osteogenic commitment represent adaptive survival response of OFMSCs to severe hypoxia and pamidronate-induced metabolic stress. Hypoxia and drug-induced OFMSC stress may be significant events governing the pathogenesis and clinical outcomes of jaw osteonecrosis.

DOI: https://doi.org/10.1016/j.joms.2021.07.027
Sci China Life Sci. 2021 Sep 07.

Control of the Hedgehog pathway by compartmentalized PKA in the primary cilium.

Eva Cai, Jingyi Zhang, Xuecai Ge.

  The Hedgehog (Hh) signaling is one of the essential signaling pathways during embryogenesis and in adults. Hh signal transduction relies on primary cilium, a specialized cell surface organelle viewed as the hub of cell signaling. Protein kinase A (PKA) has been recognized as a potent negative regulator of the Hh pathway, raising the question of how such a ubiquitous kinase specifically regulates one signaling pathway. We reviewed recent genetic, molecular and biochemical studies that have advanced our mechanistic understanding of PKA's role in Hh signaling in vertebrates, focusing on the compartmentalized PKA at the centrosome and in the primary cilium. We outlined the recently developed genetic and optical tools that can be harvested to study PKA activities during the course of Hh signal transduction.

Keywords:  Hedgehog signaling; centrosome; compartmentalized cell signaling; primary cilium; protein kinase A (PKA)

DOI:  https://doi.org/10.1007/s11427-021-1975-9
Molecules. 2021 Sep 06. pii: 5409. [Epub ahead of print]26(17):

2-IPMA Ameliorates PM2.5-Induced Inflammation by Promoting Primary Ciliogenesis in RPE Cells.

Ji Yeon Choi, Ji-Eun Bae, Joon Bum Kim, Doo Sin Jo, Na Yeon Park, Yong Hwan Kim, Ha Jung Lee, Seong Hyun Kim, So Hyun Kim, Hong Bae Jeon, Hye-Won Na, Hyungjung Choi, Hong-Yeoul Ryu, Zae Young Ryoo, Hyun-Shik Lee, Dong-Hyung Cho.

  Primary cilia mediate the interactions between cells and external stresses. Thus, dysregulation of primary cilia is implicated in various ciliopathies, e.g., degeneration of the retina caused by dysregulation of the photoreceptor primary cilium. Particulate matter (PM) can cause epithelium injury and endothelial dysfunction by increasing oxidative stress and inflammatory responses. Previously, we showed that PM disrupts the formation of primary cilia in retinal pigment epithelium (RPE) cells. In the present study, we identified 2-isopropylmalic acid (2-IPMA) as a novel inducer of primary ciliogenesis from a metabolite library screening. Both ciliated cells and primary cilium length were increased in 2-IPMA-treated RPE cells. Notably, 2-IPMA strongly promoted primary ciliogenesis and restored PM2.5-induced dysgenesis of primary cilia in RPE cells. Both excessive reactive oxygen species (ROS) generation and activation of a stress kinase, JNK, by PM2.5 were reduced by 2-IPMA. Moreover, 2-IPMA inhibited proinflammatory cytokine production, i.e., IL-6 and TNF-α, induced by PM2.5 in RPE cells. Taken together, our data suggest that 2-IPMA ameliorates PM2.5-induced inflammation by promoting primary ciliogenesis in RPE cells.

Keywords:  2-IPMA; RPE cells; inflammation; particulate matter (PM2.5); primary cilia

DOI:  https://doi.org/10.3390/molecules26175409
Reprod Toxicol. 2021 Sep 04. pii: S0890-6238(21)00139-8. [Epub ahead of print]105 136-147

Prenatal alcohol exposure disrupts Sonic hedgehog pathway and primary cilia genes in the mouse neural tube.

Karen E Boschen, Eric W Fish, Scott E Parnell.

  Neurulation-stage alcohol exposure (NAE; embryonic day [E] 8-10) is associated with midline craniofacial and CNS defects that likely arise from disruption of morphogen pathways, such as Sonic hedgehog (Shh). Notably, midline anomalies are also a hallmark of genetic ciliopathies such as Joubert syndrome. We tested whether NAE alters Shh pathway signaling and the number and function of primary cilia, organelles critical for Shh pathway transduction. Female C57BL/6 J mice were administered two doses of alcohol (2.9 g/kg/dose) or vehicle on E9. Embryos were collected 6, 12, or 24 h later, and changes to Shh, cell cycle genes, and primary cilia were measured in the rostroventral neural tube (RVNT). Within the first 24 h post-NAE, reductions in Shh pathway and cell cycle gene expression and the ratio of Gli3 forms in the full-length activator state were observed. RVNT volume and cell layer width were reduced at 12 h. In addition, altered expression of multiple cilia-related genes was observed at 6 h post-NAE. As a further test of cilia gene-ethanol interaction, mice heterozygous for Kif3a exhibited perturbed behavior during adolescence following NAE compared to vehicle-treated mice, and Kif3a heterozygosity exacerbated the hyperactive effects of NAE on exploratory activity. These data demonstrate that NAE downregulates the Shh pathway in a region of the neural tube that gives rise to alcohol-sensitive brain structures and identifies disruption of primary cilia function, or a "transient ciliopathy", as a possible cellular mechanism of prenatal alcohol pathogenesis.

Keywords:  Cell cycle; Development; Fetal alcohol spectrum disorders; Kif3a; Neurulation

DOI:  https://doi.org/10.1016/j.reprotox.2021.09.002
Cornea. 2021 Oct 01. 40(10): 1225-1228

A Close Look at the Clinical Efficacy of Rho-Associated Protein Kinase Inhibitor Eye Drops for Fuchs Endothelial Corneal Dystrophy.

Shigeru Kinoshita, Kathryn A Colby, Friedrich E Kruse.

ABSTRACT: The current understanding on the clinical efficacy of Rho-associated protein kinase (ROCK) inhibitor for treating Fuchs endothelial corneal dystrophy is summarized to clarify whether the "off-label" ROCK-inhibitor eye-drop application are appropriate. ROCK-inhibitor eye drops may eventually be deemed a cutting-edge therapy for Fuchs endothelial corneal dystrophy patients with acute corneal endothelial defect.

DOI: https://doi.org/10.1097/ICO.0000000000002642
Structure. 2021 Sep 07. pii: S0969-2126(21)00302-6. [Epub ahead of print]

Molecular mechanisms underlying the role of the centriolar CEP164-TTBK2 complex in ciliopathies.

Ivan Rosa E Silva, Lucia Binó, Christopher M Johnson, Trevor J Rutherford, David Neuhaus, Antonina Andreeva, Lukáš Čajánek, Mark van Breugel.

  Cilia formation is essential for human life. One of the earliest events in the ciliogenesis program is the recruitment of tau-tubulin kinase 2 (TTBK2) by the centriole distal appendage component CEP164. Due to the lack of high-resolution structural information on this complex, it is unclear how it is affected in human ciliopathies such as nephronophthisis. Furthermore, it is poorly understood if binding to CEP164 influences TTBK2 activities. Here, we present a detailed biochemical, structural, and functional analysis of the CEP164-TTBK2 complex and demonstrate how it is compromised by two ciliopathic mutations in CEP164. Moreover, we also provide insights into how binding to CEP164 is coordinated with TTBK2 activities. Together, our data deepen our understanding of a crucial step in cilia formation and will inform future studies aimed at restoring CEP164 functionality in a debilitating human ciliopathy.

Keywords:  CEP164; TTBK2; basal body; centriole; centrosome; cilia; ciliogenesis; ciliopathy; distal appendage; nephronophthisis

DOI:  https://doi.org/10.1016/j.str.2021.08.007
Cell Rep. 2021 Sep 07. pii: S2211-1247(21)01099-8. [Epub ahead of print]36(10): 109656

Cilium induction triggers differentiation of glioma stem cells.

Gladiola Goranci-Buzhala, Aruljothi Mariappan, Lucia Ricci-Vitiani, Natasa Josipovic, Simone Pacioni, Marco Gottardo, Johannes Ptok, Heiner Schaal, Giuliano Callaini, Krishnaraj Rajalingam, Brian Dynlacht, Kamyar Hadian, Argyris Papantonis, Roberto Pallini, Jay Gopalakrishnan.

  Glioblastoma multiforme (GBM) possesses glioma stem cells (GSCs) that promote self-renewal, tumor propagation, and relapse. Understanding the mechanisms of GSCs self-renewal can offer targeted therapeutic interventions. However, insufficient knowledge of GSCs' fundamental biology is a significant bottleneck hindering these efforts. Here, we show that patient-derived GSCs recruit elevated levels of proteins that ensure the temporal cilium disassembly, leading to suppressed ciliogenesis. Depleting the cilia disassembly complex components is sufficient to induce ciliogenesis in a subset of GSCs via relocating platelet-derived growth factor receptor-alpha (PDGFR-α) to a newly induced cilium. Importantly, restoring ciliogenesis enabled GSCs to switch from self-renewal to differentiation. Finally, using an organoid-based glioma invasion assay and brain xenografts in mice, we establish that ciliogenesis-induced differentiation can prevent the infiltration of GSCs into the brain. Our findings illustrate a role for cilium as a molecular switch in determining GSCs' fate and suggest cilium induction as an attractive strategy to intervene in GSCs proliferation.

Keywords:  brain organoids; cell cycle; cilium checkpoint; confocal 3D imaging; glioblastoma; invasion assay; primary cilium; tissue clearing

DOI:  https://doi.org/10.1016/j.celrep.2021.109656
Int J Mol Sci. 2021 Aug 28. pii: 9329. [Epub ahead of print]22(17):

Loss of Ift74 Leads to Slow Photoreceptor Degeneration and Ciliogenesis Defects in Zebrafish.

Panpan Zhu, Jingjin Xu, Yadong Wang, Chengtian Zhao.

  Cilia are microtubule-based structures projecting from the cell surface that perform diverse biological functions. Ciliary defects can cause a wide range of genetic disorders known collectively as ciliopathies. Intraflagellar transport (IFT) proteins are essential for the assembly and maintenance of cilia by transporting proteins along the axoneme. Here, we report a lack of Ift74, a core IFT-B protein, leading to ciliogenesis defects in multiple organs during early zebrafish development. Unlike rapid photoreceptor cell death in other ift-b mutants, the photoreceptors of ift74 mutants exhibited a slow degeneration process. Further experiments demonstrated that the connecting cilia of ift74 mutants were initially formed but failed to maintain, which resulted in slow opsin transport efficiency and eventually led to photoreceptor cell death. We also showed that the large amount of maternal ift74 transcripts deposited in zebrafish eggs account for the main reason of slow photoreceptor degeneration in the mutants. Together, our data suggested Ift74 is critical for ciliogenesis and that Ift proteins play variable roles in different types of cilia during early zebrafish development. To our knowledge, this is the first study to show ift-b mutant that displays slow photoreceptor degeneration in zebrafish.

Keywords:  cilia; ift74; opsin transport; photoreceptor degeneration; zebrafish

DOI:  https://doi.org/10.3390/ijms22179329
Front Pharmacol. 2021 ;12 719880

Targeting the Wnt/β-Catenin Signaling Pathway as a Potential Therapeutic Strategy in Renal Tubulointerstitial Fibrosis.

Shan-Shan Li, Qian Sun, Meng-Ru Hua, Ping Suo, Jia-Rong Chen, Xiao-Yong Yu, Ying-Yong Zhao.

  The Wnt/β-catenin signaling pathway plays important roles in embryonic development and tissue homeostasis. Wnt signaling is induced, and β-catenin is activated, associated with the development and progression of renal fibrosis. Wnt/β-catenin controls the expression of various downstream mediators such as snail1, twist, matrix metalloproteinase-7, plasminogen activator inhibitor-1, transient receptor potential canonical 6, and renin-angiotensin system components in epithelial cells, fibroblast, and macrophages. In addition, Wnt/β-catenin is usually intertwined with other signaling pathways to promote renal interstitial fibrosis. Actually, given the crucial of Wnt/β-catenin signaling in renal fibrogenesis, blocking this signaling may benefit renal interstitial fibrosis. There are several antagonists of Wnt signaling that negatively control Wnt activation, and these include soluble Fzd-related proteins, the family of Dickkopf 1 proteins, Klotho and Wnt inhibitory factor-1. Furthermore, numerous emerging small-molecule β-catenin inhibitors cannot be ignored to prevent and treat renal fibrosis. Moreover, we reviewed the knowledge focusing on anti-fibrotic effects of natural products commonly used in kidney disease by inhibiting the Wnt/β-catenin signaling pathway. Therefore, in this review, we summarize recent advances in the regulation, downstream targets, role, and mechanisms of Wnt/β-catenin signaling in renal fibrosis pathogenesis. We also discuss the therapeutic potential of targeting this pathway to treat renal fibrosis; this may shed new insights into effective treatment strategies to prevent and treat renal fibrosis.

Keywords:  Wnt/β-catenin; chronic kidney disease; natural product; renal fibrosis; traditional Chinese medicine

DOI:  https://doi.org/10.3389/fphar.2021.719880
Int J Mol Sci. 2021 Aug 30. pii: 9398. [Epub ahead of print]22(17):

Renal and Extra Renal Manifestations in Adult Zebrafish Model of Cystinosis.

Sante Princiero Berlingerio, Junling He, Lies De Groef, Harold Taeter, Tomas Norton, Pieter Baatsen, Sara Cairoli, Bianca Goffredo, Peter de Witte, Lambertus van den Heuvel, Hans J Baelde, Elena Levtchenko.

  Cystinosis is a rare, incurable, autosomal recessive disease caused by mutations in the CTNS gene. This gene encodes the lysosomal cystine transporter cystinosin, leading to lysosomal cystine accumulation in all cells of the body, with kidneys being the first affected organs. The current treatment with cysteamine decreases cystine accumulation, but does not reverse the proximal tubular dysfunction, glomerular injury or loss of renal function. In our previous study, we have developed a zebrafish model of cystinosis through a nonsense mutation in the CTNS gene and have shown that zebrafish larvae recapitulate the kidney phenotype described in humans. In the current study, we characterized the adult cystinosis zebrafish model and evaluated the long-term effects of the disease on kidney and extra renal organs through biochemical, histological, fertility and locomotor activity studies. We found that the adult cystinosis zebrafish presents cystine accumulation in various organs, altered kidney morphology, impaired skin pigmentation, decreased fertility, altered locomotor activity and ocular anomalies. Overall, our data indicate that the adult cystinosis zebrafish model reproduces several human phenotypes of cystinosis and may be useful for studying pathophysiology and long-term effects of novel therapies.

Keywords:  adult phenotypic features; cystinosis; kidney disease; renal and extra renal manifestation; zebrafish model

DOI:  https://doi.org/10.3390/ijms22179398