bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2023–04–16
twelve papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne
  1. Urinary MicroRNAs, Possible Biomarkers for Early Detection of Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD).
  2. Parasympathetic activity and total fibrotic kidney in autosomal-dominant polycystic kidney disease patients: a pilot study.
  3. Xanthogranulomatous pyelonephritis with polycystic kidney disease as a mimic of cystic renal cell carcinoma: a case report.
  4. Arl13b promotes the proliferation, migration, osteogenesis, and mechanosensation of osteoblasts.
  5. Primary Cilium Identifies a Quiescent Cell Population in the Human Intestinal Crypt.
  6. Evidence for intraflagellar transport in butterfly spermatocyte cilia.
  7. The role of Rho GTPase family in cochlear hair cells and hearing.
  8. Dynamic localization of the Na+-HCO3- co-transporter NBCn1 to the plasma membrane, centrosomes, spindle and primary cilia.
  9. Modulation of tau tubulin kinases (TTBK1 and TTBK2) impacts ciliogenesis.
  10. Neofunctionalization of ciliary BBS proteins to nuclear roles is likely a frequent innovation across eukaryotes.
  11. Calaxin stabilizes the docking of outer arm dyneins onto ciliary doublet microtubule in vertebrates.
  12. Bacterial TLR2/6 Ligands Block Ciliogenesis, Derepress Hedgehog Signaling, and Expand the Neocortex.
  1. Iran J Kidney Dis. 2023 Mar;1(2): 73-78
    Urinary MicroRNAs, Possible Biomarkers for Early Detection of Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD).
    Yaghoob Ghasemi, Alireza Mardomi, Effat Alizadeh, Hamid Tayebi Khosroshahi.
       INTRODUCTION: Autosomal dominant polycystic kidney disease (ADPKD) is a prevalent renal disorder that causes abnormal growth of renal epithelial cells. The excessive expansion of renal epithelial cells can lead to cyst formation that is associated with serious renal complications. The early diagnosis of ADPKD makes the control of the disease somehow attainable. Regarding the diagnostic potential of microRNAs (miRs) as robust clinical biomarkers, the present study aimed to examine the potential of urinary miRs in early diagnosis of ADPKD in asymptomatic patients.
    METHODS: Urine samples were obtained from 20 asymptomatic ADPKD patients and 20 healthy control individuals and the miR content of the samples was extracted and converted to cDNA for the qRT-PCR experiment. The relative expressions of miR-17, miR-21, miR-143, and miR-223 were evaluated in ADPKD cases and healthy individuals. Serum levels of kidney function markers were also evaluated in the study participants.
    RESULTS: The urine samples of patients with ADPKD demonstrated higher levels of miR-17, miR-21, and miR-143 along with a lower miR-223 level compared to the healthy control group.
    CONCLUSION: This study revealed the differential expression of the studied miRs in ADPKD patients. Detection of miRs in urinary samples might provide a useful platform for early diagnosis of ADPKD in asymptomatic patients.  DOI: 10.52547/ijkd.7281.
  2. Int Urol Nephrol. 2023 Apr 12.
    Parasympathetic activity and total fibrotic kidney in autosomal-dominant polycystic kidney disease patients: a pilot study.
    Silvia Lai, Adolfo Marco Perrotta, Valeria Panebianco, Sandro Mazzaferro, Paolo Menè, Chiara Pellicano, Francesca Tinti, Maurizio Muscaritoli, Rosario Cianci, Antonietta Gigante.
       PURPOSE: Renin-angiotensin system hyperactivation in autosomal-dominant polycystic kidney disease (ADPKD) patients leads to early hypertension. Cystic enlargement probably causes parenchymal hypoxia, renin secretion, and endothelial dysfunction. Sympathetic and parasympathetic balance is altered in this condition, especially during the night, also affecting blood pressure circadian rhythm. Aim of this study was to evaluate sympathetic/parasympathetic balance using heart rate variability (HRV) parameters and find a correlation between HRV and renal damage progression, as total kidney volume enlargement, in ADPKD patients.
    METHODS: Sixteen adult ADPKD patients were enrolled in the study. Eleven patients (68.8%) were male, and the median age was 42 years (IQR 36-47.5). HRV parameters were calculated using 24 h-ECG Holter. A kidney magnetic resonance imaging (MRI) scan 3 Tesla was performed to evaluate total kidney volume (TKV) and total fibrotic volume (TFV).
    RESULTS: A statistically significant positive linear correlation was observed between length of kidneys and frequency domain parameters as low frequency (LF) (r = 0.595, p < 0.05) and LFday (r = 0.587, p < 0.05). Moreover, a statistically significant positive linear correlation exists between high frequency (HF) and TFV (r = 0.804, p < 0.01) or height-adjusted (ha) TFV (r = 0.801, p < 0.01). Finally, we found a statistically significant positive linear correlation between HFnight and TKV (r = 0.608, p < 0.05), ha-TKV (r = 0.685, p < 0.01), TFV (r = 0.594, p < 0.05), and ha-TFV (r = 0.615, p < 0.05).
    CONCLUSION: We suppose that the increase in TKV and TFV could lead to a parasympathetic tone hyperactivation, probably in response to hypoxic stress and vasoconstriction due to cystic enlargement.
    Keywords:  Autosomal-dominant polycystic kidney disease; Heart rate variability; Renin–angiotensin–aldosterone system; Total fibrotic volume; Total kidney volume
    DOI:  https://doi.org/10.1007/s11255-023-03551-y
  3. BMC Urol. 2023 Apr 11. 23(1): 58
    Xanthogranulomatous pyelonephritis with polycystic kidney disease as a mimic of cystic renal cell carcinoma: a case report.
    Mei Yi, Yong Liu, Qi Chen.
       BACKGROUND: Xanthogranulomatous pyelonephritis (XGP) is a rare chronic pyelonephritis that often mimics other renal diseases, when combined with autosomal dominant polycystic kidney disease(ADPKD), preoperative diagnosis is exceedingly difficult. It is important for clinicians to be aware of an XGP with ADPKD since a misdiagnosis can lead to unnecessary surgical intervention.
    CASE PRESENTATION: Here, we report a case of a 66-year-old female with a history of bilateral ADPKD and urinary tract infection admitted to our hospital due to right flank pain, feeble, and low-grade fever. Contrast-enhanced ultrasound revealed a malignant mass of the right kidney suspected to be a cystic renal cell carcinoma with polycystic kidney disease. In addition, contrast-enhanced computed tomography (CT) and fluorine 18 fluorodeoxyglucose PET/CT (18F FDG PET/CT) showed similar results. Subsequently, the patient underwent a right radical nephrectomy, but histopathological examination revealed XGP with ADPKD. On the follow-up, the patient's symptoms were relieved.
    CONCLUSIONS: XGP should be kept in mind during the differential diagnosis of renal masses with ADPKD even in the absence of characteristic clinical symptoms and imaging manifestations.
    Keywords:  Case report; Cystic renal cell carcinoma; Polycystic kidney; Xanthogranulomatous pyelonephritis
    DOI:  https://doi.org/10.1186/s12894-023-01224-7
  4. Tissue Cell. 2023 Apr 11. pii: S0040-8166(23)00076-9. [Epub ahead of print]82 102088
    Arl13b promotes the proliferation, migration, osteogenesis, and mechanosensation of osteoblasts.
    Tingting Lin, Yao Sun.
      Primary cilia are microtubule-based organelles presenting on the surface of most postmitotic mammalian cells. As being signaling hubs and sensory organelles, primary cilia can respond to mechanical and chemical stimuli from the extracellular environment. Arl13b (ADP-ribosylation factor-like 13B), an atypical Arf/Arl family GTPase, was identified in genetic screening as a protein essential for maintaining the integrity of cilia and neural tubes. Previous studies on Arl13b have mostly focused on its role in the development of neural tubes, polycystic kidneys, and tumors, but no role in bone patterns was described. This study reported the essential roles of Arl13b in bone formation and osteogenic differentiation. Arl13b was highly expressed in bone tissues and osteoblasts, positively correlated with osteogenic activity during bone development. Furthermore, Arl13b was essential for primary cilium maintenance and Hedgehog signaling activation in osteoblasts. Arl13b knockdown in osteoblasts decreased the length of primary cilia and the upregulated levels of Gli1, Smo, and Ptch1 upon Smo agonist treatment. Additionally, Arl13b knockdown inhibited cell proliferation and migration. Moreover, Arl13b mediated osteogenesis and cell mechanosensation. Cyclic tension strain upregulated the Arl13b expression. Arl13b knockdown suppressed osteogenesis and mitigated cyclic tension strain-induced osteogenesis. These results suggest that Arl13b have important roles in bone formation and mechanosensation.
    Keywords:  Arl13b; Hedgehog signaling; Mechanosensation; Osteoblast; Osteogenesis; Primary cilium
    DOI:  https://doi.org/10.1016/j.tice.2023.102088
  5. Cells. 2023 Mar 31. pii: 1059. [Epub ahead of print]12(7):
    Primary Cilium Identifies a Quiescent Cell Population in the Human Intestinal Crypt.
    Blanche Sénicourt, Gabriel Cloutier, Nuria Basora, Sepideh Fallah, Andréanne Laniel, Christine Lavoie, Jean-François Beaulieu.
      Primary cilia are sensory antennae located at the cell surface which mediate a variety of extracellular signals involved in development, tissue homeostasis, stem cells and cancer. Primary cilia are found in an extensive array of vertebrae cells but can only be generated when cells become quiescent. The small intestinal epithelium is a rapidly self-renewing tissue organized into a functional unit called the crypt-villus axis, containing progenitor and differentiated cells, respectively. Terminally differentiated villus cells are notoriously devoid of primary cilia. We sought to determine if intestinal crypts contain a quiescent cell population that could be identified by the presence of primary cilia. Here we show that primary cilia are detected in a subset of cells located deep in the crypts slightly above a Paneth cell population. Using a normal epithelial proliferative crypt cell model, we show that primary cilia assembly and activity correlate with a quiescent state. These results provide further evidence for the existence of a quiescent cell population in the human small intestine and suggest the potential for new modes of regulation in stem cell dynamics.
    Keywords:  BMI1; GLI; HIEC-6 cell line; Hedgehog pathway; intestinal epithelial cells; patched; primary cilium; stem cells; tubulin
    DOI:  https://doi.org/10.3390/cells12071059
  6. Cytoskeleton (Hoboken). 2023 Apr 10.
    Evidence for intraflagellar transport in butterfly spermatocyte cilia.
    Marco Gottardo, Maria Giovanna Riparbelli, Giuliano Callaini, Timothy L Megraw.
      In the model organism insect Drosophila melanogaster short cilia assemble on spermatocytes that elaborate into 1.8 mm long flagella during spermatid differentiation. A unique feature of these cilia/flagella is their lack of dependence on intraflagellar transport (IFT) for their assembly. Here, we show that in the common butterfly Pieris brassicae, the spermatocyte cilia are exceptionally long: about 40 μm compared to less than 1 μm in Drosophila. By transmission electron microscopy, we show that P. brassicae spermatocytes display several features not found in melanogaster, including compelling evidence of IFT structures and features of motile cilia.
    Keywords:  Pieris; centrosome; cilia; flagella; intraflagellar transport; spermatocyte
    DOI:  https://doi.org/10.1002/cm.21755
  7. Neural Regen Res. 2023 Oct;18(10): 2167-2172
    The role of Rho GTPase family in cochlear hair cells and hearing.
    Yu-Bei Dai, Xiang Gao, Dong Liu, Jie Gong.
      Rho GTPases are essential regulators of the actin cytoskeleton. They are involved in various physiological and biochemical processes such as the regulation of cytoskeleton dynamics, development, proliferation, survival, and regeneration. During the development of cochlear hair cells, Rho GTPases are activated by various extracellular signals through membrane receptors to further stimulate multiple downstream effectors. Specifically, RhoA, Cdc42, and Rac1, members of the classical subfamily of the Rho GTPase family, regulate the development and maintenance of cilia by inducing the polymerization of actin monomers and stabilizing actin filaments. In addition, they also regulate the normal morphology orientation of ciliary bundles in auditory hair cells, which is an important element of cell polarity regulation. Moreover, the actin-related pathways mediated by RhoA, Cdc42, and Rac1 also play a role in the motility of outer hair cells, indicating that the function of Rho GTPases is crucial in the highly polar auditory sensory system. In this review, we focus on the expression of RhoA, Cdc42, and Rac1 in cochlear hair cells and how these small molecules participate in ciliary bundle morphogenesis and cochlear hair cell movement. We also discuss the progress of current research investigating the use of these small molecules as drug targets for deafness treatment.
    Keywords:  Rho GTPases; actin assembly; auditory sensory neurons; cell polarity; cell proliferation; electromotility; hair cell; hearing loss; morphogenesis; stereocilia
    DOI:  https://doi.org/10.4103/1673-5374.369101
  8. J Cell Sci. 2023 Apr 01. pii: jcs260687. [Epub ahead of print]136(7):
    Dynamic localization of the Na+-HCO3- co-transporter NBCn1 to the plasma membrane, centrosomes, spindle and primary cilia.
    Marc Severin, Emma Lind Pedersen, Magnus Thane Borre, Ida Axholm, Frederik Bendix Christiansen, Muthulakshmi Ponniah, Dominika Czaplinska, Tanja Larsen, Luis Angel Pardo, Stine Falsig Pedersen.
      Finely tuned regulation of transport protein localization is vital for epithelial function. The Na+-HCO3- co-transporter NBCn1 (also known as SLC4A7) is a key contributor to epithelial pH homeostasis, yet the regulation of its subcellular localization is not understood. Here, we show that a predicted N-terminal β-sheet and short C-terminal α-helical motif are essential for NBCn1 plasma membrane localization in epithelial cells. This localization was abolished by cell-cell contact disruption, and co-immunoprecipitation (co-IP) and proximity ligation (PLA) revealed NBCn1 interaction with E-cadherin and DLG1, linking it to adherens junctions and the Scribble complex. NBCn1 also interacted with RhoA and localized to lamellipodia and filopodia in migrating cells. Finally, analysis of native and GFP-tagged NBCn1 localization, subcellular fractionation, co-IP with Arl13B and CEP164, and PLA of NBCn1 and tubulin in mitotic spindles led to the surprising conclusion that NBCn1 additionally localizes to centrosomes and primary cilia in non-dividing, polarized epithelial cells, and to the spindle, centrosomes and midbodies during mitosis. We propose that NBCn1 traffics between lateral junctions, the leading edge and cell division machinery in Rab11 endosomes, adding new insight to the role of NBCn1 in cell cycle progression.
    Keywords:  Acid-base transport; Cell polarity; Cell–cell adhesion; Mitosis; Primary cilium; Scribble complex
    DOI:  https://doi.org/10.1242/jcs.260687
  9. Sci Rep. 2023 Apr 14. 13(1): 6118
    Modulation of tau tubulin kinases (TTBK1 and TTBK2) impacts ciliogenesis.
    Frances M Bashore, Ariana B Marquez, Apirat Chaikuad, Stefanie Howell, Andrea S Dunn, Alvaro A Beltran, Jeffery L Smith, David H Drewry, Adriana S Beltran, Alison D Axtman.
      Tau tubulin kinase 1 and 2 (TTBK1/2) are highly homologous kinases that are expressed and mediate disease-relevant pathways predominantly in the brain. Distinct roles for TTBK1 and TTBK2 have been delineated. While efforts have been devoted to characterizing the impact of TTBK1 inhibition in diseases like Alzheimer's disease and amyotrophic lateral sclerosis, TTBK2 inhibition has been less explored. TTBK2 serves a critical function during cilia assembly. Given the biological importance of these kinases, we designed a targeted library from which we identified several chemical tools that engage TTBK1 and TTBK2 in cells and inhibit their downstream signaling. Indolyl pyrimidinamine 10 significantly reduced the expression of primary cilia on the surface of human induced pluripotent stem cells (iPSCs). Furthermore, analog 10 phenocopies TTBK2 knockout in iPSCs, confirming a role for TTBK2 in ciliogenesis.
    DOI:  https://doi.org/10.1038/s41598-023-32854-4
  10. iScience. 2023 Apr 21. 26(4): 106410
    Neofunctionalization of ciliary BBS proteins to nuclear roles is likely a frequent innovation across eukaryotes.
    Alexander Ewerling, Vanessa Maissl, Bill Wickstead, Helen Louise May-Simera.
      The eukaryotic BBSome is a transport complex within cilia and assembled by chaperonin-like BBS proteins. Recent work indicates nuclear functions for BBS proteins in mammals, but it is unclear how common these are in extant proteins or when they evolved. We screened for BBS orthologues across a diverse set of eukaryotes, consolidated nuclear association via signal sequence predictions and permutation analysis, and validated nuclear localization in mammalian cells via fractionation and immunocytochemistry. BBS proteins are-with exceptions-conserved as a set in ciliated species. Predictions highlight five most likely nuclear proteins and suggest that nuclear roles evolved independently of nuclear access during mitosis. Nuclear localization was confirmed in human cells. These findings suggest that nuclear BBS functions are potentially not restricted to mammals, but may be a common frequently co-opted eukaryotic feature. Understanding the functional spectrum of BBS proteins will help elucidating their role in gene regulation, development, and disease.
    Keywords:  Cell biology; Evolutionary biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2023.106410
  11. Elife. 2023 Apr 14. pii: e84860. [Epub ahead of print]12
    Calaxin stabilizes the docking of outer arm dyneins onto ciliary doublet microtubule in vertebrates.
    Hiroshi Yamaguchi, Motohiro Morikawa, Masahide Kikkawa.
      Outer arm dynein (OAD) is the main force generator of ciliary beating. Although OAD loss is the most frequent cause of human primary ciliary dyskinesia, the docking mechanism of OAD onto the ciliary doublet microtubule (DMT) remains elusive in vertebrates. Here, we analyzed the functions of Calaxin/Efcab1 and Armc4, the two of five components of vertebrate OAD-DC (docking complex), using zebrafish spermatozoa and cryo-electron tomography. Mutation of armc4 caused complete loss of OAD, whereas mutation of calaxin caused only partial loss of OAD. Detailed structural analysis revealed that calaxin-/- OADs are tethered to DMT through DC components other than Calaxin, and that recombinant Calaxin can autonomously rescue the deficient DC structure and the OAD instability. Our data demonstrate the discrete roles of Calaxin and Armc4 in the OAD-DMT interaction, suggesting the stabilizing process of OAD docking onto DMT in vertebrates.
    Keywords:  cell biology; molecular biophysics; structural biology; zebrafish
    DOI:  https://doi.org/10.7554/eLife.84860
  12. mBio. 2023 Apr 13. e0051023
    Bacterial TLR2/6 Ligands Block Ciliogenesis, Derepress Hedgehog Signaling, and Expand the Neocortex.
    Beth Mann, Jeremy Chase Crawford, Kavya Reddy, Josi Lott, Yong Ha Youn, Geli Gao, Cliff Guy, Ching-Heng Chou, Daniel Darnell, Sanchit Trivedi, Perrine Bomme, Allister J Loughran, Paul G Thomas, Young-Goo Han, Elaine I Tuomanen.
      Microbial components have a range of direct effects on the fetal brain. However, little is known about the cellular targets and molecular mechanisms that mediate these effects. Neural progenitor cells (NPCs) control the size and architecture of the brain and understanding the mechanisms regulating NPCs is crucial to understanding brain developmental disorders. We identify ventricular radial glia (vRG), the primary NPC, as the target of bacterial cell wall (BCW) generated during the antibiotic treatment of maternal pneumonia. BCW enhanced proliferative potential of vRGs by shortening the cell cycle and increasing self-renewal. Expanded vRGs propagated to increase neuronal output in all cortical layers. Remarkably, Toll-like receptor 2 (TLR2), which recognizes BCW, localized at the base of primary cilia in vRGs and the BCW-TLR2 interaction suppressed ciliogenesis leading to derepression of Hedgehog (HH) signaling and expansion of vRGs. We also show that TLR6 is an essential partner of TLR2 in this process. Surprisingly, TLR6 alone was required to set the number of cortical neurons under healthy conditions. These findings suggest that an endogenous signal from TLRs suppresses cortical expansion during normal development of the neocortex and that BCW antagonizes that signal through the TLR2/cilia/HH signaling axis changing brain structure and function. IMPORTANCE Fetal brain development in early gestation can be impacted by transplacental infection, altered metabolites from the maternal microbiome, or maternal immune activation. It is less well understood how maternal microbial subcomponents that cross the placenta, such as bacterial cell wall (BCW), directly interact with fetal neural progenitors and neurons and affect development. This scenario plays out in the clinic when BCW debris released during antibiotic therapy of maternal infection traffics to the fetal brain. This study identifies the direct interaction of BCW with TLR2/6 present on the primary cilium, the signaling hub on fetal neural progenitor cells (NPCs). NPCs control the size and architecture of the brain and understanding the mechanisms regulating NPCs is crucial to understanding brain developmental disorders. Within a window of vulnerability before the appearance of fetal immune cells, the BCW-TLR2/6 interaction results in the inhibition of ciliogenesis, derepression of Sonic Hedgehog signaling, excess proliferation of neural progenitors, and abnormal cortical architecture. In the first example of TLR signaling linked to Sonic Hedgehog, BCW/TLR2/6 appears to act during fetal brain morphogenesis to play a role in setting the total cell number in the neocortex.
    Keywords:  Toll-like receptors; cell wall; hedgehog signaling; neocortex
    DOI:  https://doi.org/10.1128/mbio.00510-23
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