bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2023–07–16
seven papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne
  1. Uncovering cilia function in glial development.
  2. Spatiotemporal Mapping of Brain Cilia Length and Orientation Reveals Region-Specific Oscillation.
  3. Clinical Characteristics and Courses of Patients With Autosomal Recessive Polycystic Kidney Disease-Mimicking Phenocopies.
  4. Culture of Three-Dimensional Madin-Darby Canine Kidney (MDCK) Cysts for In Vitro Drug Testing in Polycystic Kidney Disease.
  5. Predicting the Risk of Progression in Indian ADPKD Cohort using PROPKD Score - A Single-Center Retrospective Study.
  6. Compound heterozygous IFT81 variations in a skeletal ciliopathy patient cause Bardet-Biedl syndrome-like ciliary defects.
  7. A Ciliary Branched Actin Network Drives Photoreceptor Disc Morphogenesis.
  1. Ann Hum Genet. 2023 Jul 10.
    Uncovering cilia function in glial development.
    Rachel M Bear, Tamara Caspary.
      Primary cilia play critical roles in regulating signaling pathways that underlie several developmental processes. In the nervous system, cilia are known to regulate signals that guide neuron development. Cilia dysregulation is implicated in neurological diseases, and the underlying mechanisms remain poorly understood. Cilia research has predominantly focused on neurons and has overlooked the diverse population of glial cells in the brain. Glial cells play essential roles during neurodevelopment, and their dysfunction contributes to neurological disease; however, the relationship between cilia function and glial development is understudied. Here we review the state of the field and highlight the glial cell types where cilia are found and the ciliary functions that are linked to glial development. This work uncovers the importance of cilia in glial development and raises outstanding questions for the field. We are poised to make progress in understanding the function of glial cilia in human development and their contribution to neurological diseases.
    Keywords:  cilia; glia; neurodevelopment
    DOI:  https://doi.org/10.1111/ahg.12519
  2. bioRxiv. 2023 Jun 29. pii: 2023.06.28.546950. [Epub ahead of print]
    Spatiotemporal Mapping of Brain Cilia Length and Orientation Reveals Region-Specific Oscillation.
    Roudabeh Vakil Monfared, Sherif Abdelkarim, Pieter Derdeyn, Kiki Chen, Hanting Wu, Kenneth Leong, Tiffany Chang, Justine Lee, Sara Versales, Surya M Nauli, Kevin Beier, Pierre Baldi, Amal Alachkar.
      Primary cilia, dynamic microtubule-based organelles, play crucial roles in cellular homeostasis, development, and signal transduction. Despite the recognition of their importance, the complex dynamics of cilia, particularly their potential roles in the brain, circadian rhythms, and neurological processes, remain largely unexplored. Here, we conduct a comprehensive exploration of the spatiotemporal variability and circadian rhythms of primary cilia length and orientation across 22 distinct mouse brain regions by analyzing over 10 million individual cilia. We found that both cilia length and angle in numerous brain regions exhibit very dynamic changes over a 24 hour period. Specifically, the fluctuations in cilia length and orientation have notable peaks during both light and dark phases. Our comprehensive analysis further revealed that cilia display a distinct distribution at 45° increments, indicating that the orientation of cilia within the brain is not random but rather prefers specific orientations. Collectively, these findings provide invaluable insights into the complex interplay between cilia dynamics, circadian rhythms, and brain function. Our data also highlight cilia's significance in the brain's response to environmental changes and regulation of time-dependent physiological processes.
    Abstract Figure:
    DOI:  https://doi.org/10.1101/2023.06.28.546950
  3. Kidney Int Rep. 2023 Jul;8(7): 1449-1454
    Clinical Characteristics and Courses of Patients With Autosomal Recessive Polycystic Kidney Disease-Mimicking Phenocopies.
    Abdul A Halawi, Kathrin Burgmaier, Anja K Buescher, Ismail Dursun, Florian Erger, Matthias Galiano, Michaela Gessner, Ibrahim Gökce, Djalila Mekahli, Sevgi Mir, Lukasz Obrycki, Rukshana Shroff, Stella Stabouli, Maria Szczepanska, Ana Teixeira, Lutz T Weber, Andrea Wenzel, Elke Wühl, Katarzyna Zachwieja, Jörg Dötsch, Franz Schaefer, Max C Liebau.
      
    Keywords:  PKD1; PKD2; PKHD1; TMEM67; ciliopathies; polycystic kidney disease
    DOI:  https://doi.org/10.1016/j.ekir.2023.04.006
  4. Methods Mol Biol. 2023 ;2664 135-144
    Culture of Three-Dimensional Madin-Darby Canine Kidney (MDCK) Cysts for In Vitro Drug Testing in Polycystic Kidney Disease.
    Sayanthooran Saravanabavan, Gopala K Rangan.
      The formation and growth of kidney cysts (fluid-filled structures lined by epithelial cells) is the primary pathological abnormality in polycystic kidney disease (PKD). Multiple molecular pathways are disrupted in kidney epithelial precursor cells, which lead to altered planar cell polarity, increased proliferation, and fluid secretion, which together with extracellular matrix remodelling culminates in the formation and growth of cysts. Three-dimensional (3D) in vitro cyst models serve as suitable preclinical models to screen candidate drugs for PKD. Madin-Darby Canine Kidney (MDCK) epithelial cells form polarized monolayers with a fluid-filled lumen when suspended in a collagen gel, and their growth is accelerated with the addition of forskolin, a cyclic adenosine monophosphate (cAMP) agonist. Candidate drugs for PKD can be screened for their ability to modulate growth of forskolin-treated MDCK cysts by measuring and quantifying cyst images acquired at progressive timepoints. In this chapter, we describe the detailed methods for the culture and growth of MDCK cysts in a collagen matrix and a protocol for their use in testing candidate drugs to prevent cyst formation and growth.
    Keywords:  Collagen matrix; Cyst growth; Drug screening; In vitro cysts; PKD; Preclinical model
    DOI:  https://doi.org/10.1007/978-1-0716-3179-9_10
  5. Indian J Nephrol. 2023 May-Jun;33(3):33(3): 195-201
    Predicting the Risk of Progression in Indian ADPKD Cohort using PROPKD Score - A Single-Center Retrospective Study.
    Shivendra Singh, H C Sreenidhi, Parimal Das, Chandra Devi.
      
    Background: With the variable genotype-phenotype expression of autosomal dominant polycystic kidney disease (ADPKD) and availability of novel targeted therapies, it is important to find predictors for rapid progression. The PROPKD score, consisting of genetic and clinical parameters like sex, hypertension, and urological events, is a useful tool in predicting the risk of progression. This study was aimed to determine the risk of ADPKD progression in Indian patients using the PROPKD score.
    Materials and Methods: A retrospective study was done from 2006 to 2021. ADPKD patients with ESRD were included in the study. Scoring was done as per the PROPKD score as follows: male sex: 1, onset of hypertension before 35 years: 2, first urological event before 35 years: 2, PKD1 truncating mutation: 4, PKD1 non-truncating mutation: 2, and PKD2 mutation: 0. Two types of risk classifications were done as follows: (a) considering the clinical variables in all 73 patients (male sex, onset of hypertension before 35 years, and first urological event before 35 years), they were classified into three risk groups: low-risk group (0-1), intermediate-risk group (2-3), and high-risk group (4-5) and (b) considering the clinical variables and type of mutation in 39 patients, they were classified into three risk groups: low-risk group (0-3), intermediate-risk group (4-6), and high-risk group (7-9).
    Results: Total number of patients included was 73, with the median age at ESRD being 54 years. High-risk group of clinical variables with hazard ratio (HR) of 4.570 (2.302-9.075, P < 0.001) and high-risk group of the PROPKD score with HR of 6.594 (1.868-23.284, P = 0.003) were associated with early ESRD. High-risk groups of both classifications were associated with early ESRD.
    Conclusion: High-risk groups based on the PROPKD scoring and clinical variables were associated with early progression to ESRD.
    Keywords:  ADPKD; PKD1 and PKD2; PROPKD; progression to ESRD
    DOI:  https://doi.org/10.4103/ijn.ijn_69_22
  6. Hum Mol Genet. 2023 Jul 10. pii: ddad112. [Epub ahead of print]
    Compound heterozygous IFT81 variations in a skeletal ciliopathy patient cause Bardet-Biedl syndrome-like ciliary defects.
    Koshi Tasaki, Zhuang Zhou, Yamato Ishida, Yohei Katoh, Kazuhisa Nakayama.
      Owing to their crucial roles in development and homeostasis, defects in cilia cause ciliopathies with diverse clinical manifestations. The intraflagellar transport (IFT) machinery, containing the IFT-A and IFT-B complexes, mediates not only the intraciliary bidirectional trafficking but also import and export of ciliary proteins together with the kinesin-2 and dynein-2 motor complexes. The BBSome, containing eight subunits encoded by causative genes of Bardet-Biedl syndrome (BBS), connects the IFT machinery to ciliary membrane proteins to mediate their export from cilia. Although mutations in subunits of the IFT-A and dynein-2 complexes cause skeletal ciliopathies, mutations in some IFT-B subunits are also known to cause skeletal ciliopathies. We here show that compound heterozygous variations of an IFT-B subunit, IFT81, found in a patient with skeletal ciliopathy cause defects in its interactions with other IFT-B subunits, and in ciliogenesis and ciliary protein trafficking when one of the two variants was expressed in IFT81-knockout (KO) cells. Notably, we found that IFT81-KO cells expressing IFT81 (Δ490-519), which lacks the binding site for the IFT25-IFT27 dimer, causes ciliary defects reminiscent of those found in BBS cells and those in IFT74-KO cells expressing a BBS variant of IFT74, which forms a heterodimer with IFT81. In addition, IFT81-KO cells expressing IFT81 (Δ490-519) in combination with the other variant, IFT81 (L645*), which mimics the cellular conditions of the above skeletal ciliopathy patient, demonstrated essentially the same phenotype as those expressing only IFT81 (Δ490-519). Thus, our data indicate that BBS-like defects can be caused by skeletal ciliopathy variants of IFT81.
    DOI:  https://doi.org/10.1093/hmg/ddad112
  7. Adv Exp Med Biol. 2023 ;1415 507-511
    A Ciliary Branched Actin Network Drives Photoreceptor Disc Morphogenesis.
    William J Spencer, Vadim Y Arshavsky.
      The light-detecting organelle of the photoreceptor cell is a modified primary cilium, called the outer segment. The outer segment houses hundreds of light-sensitive membrane, "discs," that are continuously renewed by the constant formation of new discs at the outer segment base and the phagocytosis of old ones from outer segment tips by the retinal pigment epithelium. In this chapter, we describe how an actin cytoskeleton network, residing precisely at the site of disc formation, provides the driving force that pushes out the ciliary plasma membrane to form each disc evagination that subsequently can mature into a bona fide disc. We highlight the functions of actin-binding proteins, particularly PCARE and Arp2/3, that are known to participate in disc formation. Finally, we describe a working model of disc formation built upon the many studies focusing on the role of actin during disc morphogenesis.
    Keywords:  Actin cytoskeleton; Cilia; Outer segment; Photoreceptor; Vision
    DOI:  https://doi.org/10.1007/978-3-031-27681-1_74
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