bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2022–12–18
thirteen papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne
  1. FOXA1 is a transcriptional activator of Odf2/Cenexin and regulates primary ciliation.
  2. Overexpression of Notch Signaling in Renin Cells Leads to a Polycystic Kidney Phenotype.
  3. Hedgehog signaling regulates Wolffian duct development through the primary cilium.
  4. Activation of tolvaptan-responsive T-cell clones with the structurally-related mozavaptan.
  5. Ckb and Ybx2 interact with Ribc2 and are necessary for the ciliary beating of multi-cilia.
  6. Protection of primary cilia is an effective countermeasure against the impairment of osteoblast function induced by simulated microgravity.
  7. Combined Liver-Kidney Transplant for Juvenile Polycystic Kidney Disease and Concomitant Hereditary Factor V Deficiency.
  8. Caspase-1 and the inflammasome promote polycystic kidney disease progression.
  9. Cilia bent out of shape over dysfunctional astrocyte mitochondria.
  10. LIPUS accelerates bone regeneration via HDAC6-mediated ciliogenesis.
  11. Novel ROCK Inhibitors, Sovesudil and PHP-0961, Enhance Proliferation, Adhesion and Migration of Corneal Endothelial Cells.
  12. Primary cilia: The central role in the electromagnetic field induced bone healing.
  13. Mass-Spec, Cryo-EM and AI join forces for a close look at the transporter complex in cilia.
  1. Sci Rep. 2022 Dec 12. 12(1): 21468
    FOXA1 is a transcriptional activator of Odf2/Cenexin and regulates primary ciliation.
    Christian Carl Czerny, Anett Borschel, Mingfang Cai, Madeline Otto, Sigrid Hoyer-Fender.
      Primary cilia are sensory organelles essential for embryonic and postnatal development, and tissue homeostasis in adulthood. They are generated in a cell cycle-dependent manner and found on most cells of the body. Although cilia formation is intensively investigated virtually nothing is known about the transcriptional regulation of primary ciliation. We used here Odf2/Cenexin, encoding a protein of the mother centriole and the basal body that is mandatory for primary cilia formation, as the target gene for the identification of transcriptional activators. We identified a consensus binding site for Fox transcription factors (TFs) in its promoter region and focused here on the Fox family. We found transcriptional activation of Odf2 neither by FOXO TFs nor by the core TF for multiciliation, FOXJ1. However, we identified FOXA1 as a transcriptional activator of Odf2 by reporter gene assays and qRT-PCR, and showed by qWB that Foxa1 knockdown caused a decrease in ODF2 and CP110 proteins. We verified the binding sequence of FOXA1 in the Odf2 promoter by ChIP. Finally, we demonstrated that knockdown of FOXA1 affected primary cilia formation. We, thus, showed for the first time, that FOXA1 regulates primary ciliation by transcriptional activation of ciliary genes.
    DOI:  https://doi.org/10.1038/s41598-022-25966-w
  2. Clin Sci (Lond). 2022 Dec 12. pii: CS20220496. [Epub ahead of print]
    Overexpression of Notch Signaling in Renin Cells Leads to a Polycystic Kidney Phenotype.
    Brian C Belyea, Fang Xu, Margaret Wiltsie, Hayes Fountain, Jenifer Charlton, Agnes Fogo, Maria Luisa Soledad Sequeira-Lopez, Roberto Ariel Gomez.
      Polycystic kidney disease (PKD) is an inherited disorder that results in large kidneys, numerous fluid-filled cysts, and ultimately end stage kidney disease.  PKD is either autosomal dominant caused by mutations in PKD1 or PKD2 genes or autosomal recessive caused by mutations in the PKHD1 or DZIP1L genes.  While the genetic basis of PKD is known, the downstream molecular mechanisms and signaling pathways which lead to deregulation of proliferation, apoptosis, and differentiation are not completely understood.  The Notch pathway plays critical roles during kidney development including directing differentiation of various progenitor cells, and aberrant Notch signaling results in gross alternations in cell fate.  In this study, we generated and studied transgenic mice which have overexpression of an intracellular fragment of mouse Notch1 ("NotchIC") in renin-expressing cells.  Mice with overexpression of NotchIC in renin-expressing cells developed numerous fluid-filled cysts, enlarged kidneys, anemia, renal insufficiency, and early death.  Cysts developed in both glomeruli and proximal tubules, had increased proliferation marks, and had increased levels of Myc.  This work implicates the Notch signaling pathway as a central player in PKD pathogenesis and suggests the Notch-Myc axis may be an important target for therapeutic intervention.
    Keywords:  notch signalling pathway; renal physiology; renin-angiotensin system
    DOI:  https://doi.org/10.1042/CS20220496
  3. Biol Reprod. 2022 Dec 15. pii: ioac210. [Epub ahead of print]
    Hedgehog signaling regulates Wolffian duct development through the primary cilium.
    Maíra Bianchi Rodrigues Alves, Laura Girardet, Céline Augière, Kyeong Hye Moon, Camille Lavoie-Ouellet, Agathe Bernet, Denis Soulet, Ezequiel Calvo, Maria E Teves, Charles Joly Beauparlant, Arnaud Droit, Alexandre Bastien, Claude Robert, Jinwoong Bok, Barry T Hinton, Clémence Belleannée.
      Primary cilia play pivotal roles in embryonic patterning and organogenesis through transduction of the Hedgehog signaling pathway (Hh). While mutations in Hh morphogens impair the development of the gonads and trigger male infertility, the contribution of Hh and primary cilia in the development of male reproductive ductules, including the epididymis, remains unknown. From a Pax2Cre; Ift88fl/fl knock-out mouse model, we found that primary cilia deletion is associated with imbalanced Hh signaling and morphometric changes in the Wolffian duct (WD), the embryonic precursor of the epididymis. Similar effects were observed following pharmacological blockade of primary cilia formation and Hh modulation on WD organotypic cultures. The expression of genes involved in extracellular matrix (ECM), mesenchymal-epithelial transition, canonical Hh, and WD development was significantly altered after treatments. Altogether, we identified the primary cilia-dependent Hh signaling as a master regulator of genes involved in WD development. This provides new insights regarding the etiology of sexual differentiation and male infertility issues.
    Keywords:  Epididymis; GLI factors; Hedgehog signaling; IFT88; Wolffian duct; embryo development; male infertility; mouse; organotypic cultures; primary cilia
    DOI:  https://doi.org/10.1093/biolre/ioac210
  4. Toxicol Lett. 2023 Jan 15. pii: S0378-4274(22)01801-X. [Epub ahead of print]373 148-151
    Activation of tolvaptan-responsive T-cell clones with the structurally-related mozavaptan.
    Sean Hammond, Xiaoli Meng, Merrie Mosedale, Dean J Naisbitt.
      Tolvaptan is an effective drug for the treatment of autosomal dominant polycystic kidney disease, but its use is associated with a significant risk of T-cell-mediated liver injury in a small number of patients. An important clinical conundrum following the contraindication of tolvaptan is whether administration of agents of similar pharmacological action and structure will be tolerated. Herein, we addressed this question through the exposure of tolvaptan-responsive T-cell clones to similar pharmaceutical agents. Whilst lixivaptan and conivaptan did not activate tolvaptan-responsive T-cells, mozavaptan evoked proliferative responses comparable with tolvaptan itself, indicating that there may be collateral immunological intolerance to this compound as a product of sensitization to tolvaptan.
    Keywords:  ADPKD; Drug-induced liver injury; Human; Mozavaptan; T-lymphocytes; Tolvaptan
    DOI:  https://doi.org/10.1016/j.toxlet.2022.11.017
  5. Genes Genomics. 2022 Dec 12.
    Ckb and Ybx2 interact with Ribc2 and are necessary for the ciliary beating of multi-cilia.
    Keun Yeong Kwon, Hyeongsun Jeong, Dong Gil Jang, Taejoon Kwon, Tae Joo Park.
       BACKGROUND: Motile cilia in a vertebrate are important to sustaining activities of life. Fluid flow on the apical surface of several tissues, including bronchial epithelium, ependymal epithelium, and fallopian tubules is generated by the ciliary beating of motile cilia. Multi-ciliated cells in ependymal tissue are responsible for the circulation of cerebrospinal fluid (CSF), which is essential for the development and homeostasis of the central nervous system, and airway tissues are protected from external contaminants by cilia-driven mucosal flow over the top of the airway epithelium.
    OBJECTIVE: A previous study reported that reduction of Ribc2 protein leads to disruption of ciliary beating in multi-ciliated cells. However, knowledge regarding the molecular function of Ribc2 is limited, thus currently available information is also limited. Therefore, we evaluated the importance of proteins involved in the interaction with Ribc2 in the process of ciliary beating.
    METHODS: Immunoprecipitation and mass spectrometry analysis was performed for the discovery of proteins involved in the interaction with Ribc2. Expression of the target gene was inhibited by injection of antisense morpholinos and measurement of the fluid flow on the embryonic epidermis of Xenopus was performed using fluorescent beads for examination of the ciliary beating of multi cilia. In addition, the flag-tagged protein was expressed by injection of mRNA and the changes in protein localization in the cilia were measured by immunostaining and western blot analysis for analysis of the molecular interaction between Ribc2 and Ribc2 binding proteins in multi-cilia.
    RESULTS: The IP/MS analysis identified Ckb and Ybx2 as Ribc2 binding proteins and our results showed that localization of both Ckb and Ybx2 occurs at the axoneme of multi-cilia on the embryonic epithelium of Xenopus laevis. In addition, our findings confirmed that knock-down of Ckb or Ybx2 resulted in abnormal ciliary beating and reduction of cilia-driven fluid flow on multi-cilia of Xenopus laevis. In addition, significantly decreased localization of Ckb or Ybx2 in the ciliary axoneme was observed in Ribc2-depleted multi-cilia.
    CONCLUSION: Ckb and Ybx2 are involved in the interaction with Ribc2 and are necessary for the ciliary beating of multi-cilia.
    Keywords:  Cilia; Ciliary beating; Ckb; Ribc2; Ybx2
    DOI:  https://doi.org/10.1007/s13258-022-01350-w
  6. J Cell Mol Med. 2022 Dec 13.
    Protection of primary cilia is an effective countermeasure against the impairment of osteoblast function induced by simulated microgravity.
    Jing Liu, Fei-Fan Leng, Yu-Hai Gao, Wen-Fang He, Ju-Fang Wang, Cory J Xian, Hui-Ping Ma, Ke-Ming Chen.
      The molecular mechanism for the microgravity-induced decrease in bone formation remains unclear and there is a lack of effective specific preventative therapies. We recently reported that primary cilia of osteoblasts became shorter and even disappeared when the cells were exposed to random positioning machine (RPM)-simulated microgravity and that the microgravity-induced loss of osteogenic potential of osteoblasts could be attenuated when the resorption of primary cilia was prevented by treatment with 0.1 μM cytochalasin D. In the current study, it was further found that the loss of the osteogenic capacity of rat calvarial osteoblasts (ROBs) was associated with the inhibition of the BMP-2/Smad1/5/8 signalling pathway, of which most of the signalling proteins including BMP-2, BMPRII, Smad1/5/8 and p-Smad1/5/8 were found localized to primary cilia. Accompanying the resorption of primary cilia following the cells being exposed to simulated microgravity, the expression levels of these signalling proteins were reduced significantly. Furthermore, the expression of miRNA-129-3p, a microRNA previously reported to control cilium biogenesis, was found to be reduced quickly and changed in a similar tendency with the length of primary cilia. Moreover, overexpression of miRNA-129-3p in ROBs significantly attenuated microgravity-induced inhibition of BMP-2 signalling and loss of osteogenic differentiation and mineralization. These results indicated the important role of miRNA-129-3p in microgravity-induced resorption of primary cilia of osteoblasts and the potential of replenishing the miRNA-129-3p as an effective countermeasure against microgravity-induced loss of primary cilia and impairment of osteoblast function.
    Keywords:  BMP-2; miRNA-129-3p; microgravity; osteoblasts; osteogenic differentiation; primary cilia
    DOI:  https://doi.org/10.1111/jcmm.17628
  7. Exp Clin Transplant. 2022 Nov;20(11): 1043-1045
    Combined Liver-Kidney Transplant for Juvenile Polycystic Kidney Disease and Concomitant Hereditary Factor V Deficiency.
    Victur Yu, Nargus Ebrahimi, Tariq Cachalia, Andrew Jacques, Kate Wyburn, Geoffrey W McCaughan, Scott Dunkley, Michael D Crawford, Carlo Pulitano, Jerome M Laurence.
      Factor V deficiency is a congenital bleeding diathesis that, in selected cases, may be managed with liver transplant. In this case, we describe the treatment of an adult patient with kidney failure secondary to juvenile onset polycystic kidney disease who received a combined liver-kidney transplant as a method to manage the risks associated with the need for a kidney transplantin the setting of factorV deficiency and high sensitization.
    DOI:  https://doi.org/10.6002/ect.2022.0229
  8. Front Mol Biosci. 2022 ;9 971219
    Caspase-1 and the inflammasome promote polycystic kidney disease progression.
    Katherine I Swenson-Fields, Christopher J Ward, Micaila E Lopez, Shaneann Fross, Anna L Heimes Dillon, James D Meisenheimer, Adib J Rabbani, Emily Wedlock, Malay K Basu, Kyle P Jansson, Peter S Rowe, Jason R Stubbs, Darren P Wallace, Michael P Vitek, Timothy A Fields.
      We and others have previously shown that the presence of renal innate immune cells can promote polycystic kidney disease (PKD) progression. In this study, we examined the influence of the inflammasome, a key part of the innate immune system, on PKD. The inflammasome is a system of molecular sensors, receptors, and scaffolds that responds to stimuli like cellular damage or microbes by activating Caspase-1, and generating critical mediators of the inflammatory milieu, including IL-1β and IL-18. We provide evidence that the inflammasome is primed in PKD, as multiple inflammasome sensors were upregulated in cystic kidneys from human ADPKD patients, as well as in kidneys from both orthologous (PKD1 RC/RC or RC/RC) and non-orthologous (jck) mouse models of PKD. Further, we demonstrate that the inflammasome is activated in female RC/RC mice kidneys, and this activation occurs in renal leukocytes, primarily in CD11c+ cells. Knock-out of Casp1, the gene encoding Caspase-1, in the RC/RC mice significantly restrained cystic disease progression in female mice, implying sex-specific differences in the renal immune environment. RNAseq analysis implicated the promotion of MYC/YAP pathways as a mechanism underlying the pro-cystic effects of the Caspase-1/inflammasome in females. Finally, treatment of RC/RC mice with hydroxychloroquine, a widely used immunomodulatory drug that has been shown to inhibit the inflammasome, protected renal function specifically in females and restrained cyst enlargement in both male and female RC/RC mice. Collectively, these results provide evidence for the first time that the activated Caspase-1/inflammasome promotes cyst expansion and disease progression in PKD, particularly in females. Moreover, the data suggest that this innate immune pathway may be a relevant target for therapy in PKD.
    Keywords:  Caspase-1; IL-18; IL-1β; MYC; YAP; hydroxychloroquine; inflammasome; polycystic kidney disease
    DOI:  https://doi.org/10.3389/fmolb.2022.971219
  9. J Cell Biol. 2023 Jan 02. pii: e202211123. [Epub ahead of print]222(1):
    Cilia bent out of shape over dysfunctional astrocyte mitochondria.
    Rachel M Bear, Tamara Caspary.
      Mitochondrial dysfunction in astrocytes drives neurodegenerative brain pathology. In this issue, Ignatenko et al. (2022. J. Cell. Biol.https://doi.org/10.1083/jcb.202203019) discover a novel connection between cilia and mitochondria in astrocytes, whereby mitochondrial dysfunction leads to abnormal cilia structure and a motile cilia program.
    DOI:  https://doi.org/10.1083/jcb.202211123
  10. Biochem Biophys Res Commun. 2022 Dec 08. pii: S0006-291X(22)01678-3. [Epub ahead of print]641 34-41
    LIPUS accelerates bone regeneration via HDAC6-mediated ciliogenesis.
    Han Xiao, An Yan, Miao Li, Linfeng Wang, Jie Xiang.
      Delayed fracture union and nonunion are common complications of fracture encountered, while Low-intensity pulsed ultrasound (LIPUS) can stimulate bone regeneration. Still, the underlying mechanism of LIPUS on bone regeneration has been poorly understood, which resulted in varied outcomes in the clinic. Therefore, figuring out the mechanism of LIPUS on bone regeneration can lay the foundation for better use of LIPUS in clinical bone regenerative therapies. In this study, we created transgenic mice to reveal the relationship between the periosteal cells' fate and the number of ciliated cells under the LIPUS stimulation. In vitro, we isolated the periosteal cell and aim to figure out the relationship between LIPUS and HDAC6-mediated ciliogenesis and find out a potential target for LIPUS-based bone regeneration strategies. The results showed that LIPUS promoted femoral bone defect regeneration and enhanced osteogenic differentiation of Prrx1+ cells. However, these pro-effects were significantly weakened when the Prrx1+ cell's primary cilia were knocked down. Besides, LIPUS stimulated the formation of Prrx1+ cells' primary cilia in the bone defect microenvironment. In vitro, the results supported that LIPUS enhanced the osteogenic differentiation of Prrx1+ cells through HDAC6-mediated ciliogenesis. In conclusion, λ LIPUS could promote the osteogenic differentiation of Prrx1+ cells to stimulate bone regeneration and inhibit the expression of HDAC6 to increase the prevalence of primary cilia in Prrx1+ cells. LIPUS could enhance the osteogenic differentiation of Prrx1+ cells mainly through HDAC6-mediated ciliogenesis.
    Keywords:  Bone regeneration; HDAC6; LIPUS; Primary cilia; Prrx1(+) periosteal progenitors
    DOI:  https://doi.org/10.1016/j.bbrc.2022.12.010
  11. Int J Mol Sci. 2022 Nov 24. pii: 14690. [Epub ahead of print]23(23):
    Novel ROCK Inhibitors, Sovesudil and PHP-0961, Enhance Proliferation, Adhesion and Migration of Corneal Endothelial Cells.
    Kyung Wook Kim, Young Joo Shin, Sammy Chi Sam Lee.
      The loss or dysfunction of human corneal endothelial cells (hCEnCs) is a leading cause of blindness due to corneal failure. Corneal transplantation with a healthy donor cornea has been the only available treatment for corneal endothelial disease. However, the need for way to regenerate the CEnCs has been increased due to the global shortage of donor corneas. The aim of the study is to investigate whether novel Rho-kinase (ROCK) inhibitors can induce the cultivation and regeneration of hCEnCs. Cultured hCEnCs were treated with Y-27632, sovesudil, or PHP-0961 for 24 h. Cellular responses, including cell viability, cytotoxicity, proliferation, and Ki67 expression with ROCK inhibitors were evaluated. We also evaluated wound healing and cell adhesion assays. Porcine corneas were used ex vivo to evaluate the effects of Y-27632, sovesudil, and PHP-0961 on wound healing and regeneration. We performed live/dead cell assays and immunofluorescence staining for SRY (sex determining region Y)-box 2 (SOX2), β-catenin, and ZO-1 on porcine corneas after ROCK inhibitor treatments. Cell viability, cell proliferation rate, and the number of Ki67-positive cells were higher in Y-27632, sovesudil and PHP-0961 treated cells compared to the control. There was no difference in LDH cytotoxicity test between any groups. Cells treated with Y-27632, sovesudil and PHP-0961 showed faster migration, wound healing, and cell adhesion. In the porcine ex vivo experiments, wound healing, the number of live cells, and SOX2-positive cells were higher in Y-27632, sovesudil and PHP-0961 treated corneas. In all experiments, sovesudil and PHP-0961, the novel ROCK inhibitors, were equal or superior to the results of the ROCK inhibitor positive control, Y-27632. In conclusion, sovesudil and PHP-0961, novel ROCK inhibitors have the capacity to regenerate hCEnCs by enhancing cell proliferation and adhesion between cells.
    Keywords:  corneal endothelial cells; novel ROCK inhibitor; regeneration; sovesudil
    DOI:  https://doi.org/10.3390/ijms232314690
  12. Front Pharmacol. 2022 ;13 1062119
    Primary cilia: The central role in the electromagnetic field induced bone healing.
    Yangmengfan Chen, Chao Lu, Xifu Shang, Kerong Wu, Kun Chen.
      Primary cilia have emerged as the cellular "antenna" that can receive and transduce extracellular chemical/physical signals, thus playing an important role in regulating cellular activities. Although the electromagnetic field (EMF) is an effective treatment for bone fractures since 1978, however, the detailed mechanisms leading to such positive effects are still unclear. Primary cilia may play a central role in receiving EMF signals, translating physical signals into biochemical information, and initiating various signalingsignaling pathways to transduce signals into the nucleus. In this review, we elucidated the process of bone healing, the structure, and function of primary cilia, as well as the application and mechanism of EMF in treating fracture healing. To comprehensively understand the process of bone healing, we used bioinformatics to analyze the molecular change and associated the results with other studies. Moreover, this review summarizedsummarized some limitations in EMFs-related research and provides an outlook for ongoing studies. In conclusion, this review illustrated the primary cilia and related molecular mechanisms in the EMF-induced bone healing process, and it may shed light on future research.
    Keywords:  bone; electromagnetic fields; osteogenesis; primary cilia; signaling pathway
    DOI:  https://doi.org/10.3389/fphar.2022.1062119
  13. EMBO J. 2022 Dec 15. e113010
    Mass-Spec, Cryo-EM and AI join forces for a close look at the transporter complex in cilia.
    Takashi Ishikawa.
      The intraflagellar transport (IFT) complex transports components between the cytoplasm and the ciliary tip. Two studies now report on the atomic structure of IFT-B, the core of IFT, using cutting-edge technology, such as cross-linking mass spectrometry (MS), cryo-electron tomography (cryo-ET) and Alphafold2-enabled AI-based folding prediction. The 3D structure of IFT-B reveals how the 15 component proteins are arranged to stabilize this gigantic complex and suggests a dynamic interplay between the proteins.
    DOI:  https://doi.org/10.15252/embj.2022113010
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