DOCSLIB.ORG

Components of Intraflagellar Transport Complex a Function

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Components of Intraflagellar Transport Complex a Function Article Components of Intraflagellar Transport Complex A Function Independently of the Cilium to Regulate Canonical Wnt Signaling in Drosophila Graphical Abstract Authors Sophie Balmer, Aurore Dussert, Giovanna M. Collu, Elvira Benitez, Carlo Iomini, Marek Mlodzik Correspondence [email protected] In Brief Intraflagellar transport (IFT) proteins form multi-subunit protein complexes to ensure bidirectional transport within the cilium. Balmer et al. identify through a reverse genetic screen that a subset of IFT complex A proteins promotes canonical Wnt signaling independent of their ciliary function by modulation of b-catenin/Armadillo activity. Highlights d Ciliary proteins can modulate the canonical Wnt pathway independently of the cilium d IFT-A protein knockdown leads to loss of canonical Wnt- specific target gene expression d IFT-A proteins modulate Wnt signaling through the stabilization of b-cat/Arm Balmer et al., 2015, Developmental Cell 34, 705–718 September 28, 2015 ª2015 Elsevier Inc. http://dx.doi.org/10.1016/j.devcel.2015.07.016 Developmental Cell Article Components of Intraflagellar Transport Complex A Function Independently of the Cilium to Regulate Canonical Wnt Signaling in Drosophila Sophie Balmer,1,4 Aurore Dussert,1,3 Giovanna M. Collu,1 Elvira Benitez,1 Carlo Iomini,1,2 and Marek Mlodzik1,2,* 1Department of Developmental & Regenerative Biology and Graduate School of Biomedical Sciences 2Department of Ophthalmology Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA 3Present address: CNRS, UMR 6290, Institut de Ge´ ne´ tique et De´ veloppement de Rennes, Universite´ de Rennes 1, 35043 Rennes, France 4Present address: Sloan-Kettering Institute, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.devcel.2015.07.016 SUMMARY bule-based protrusions arising from a modified centriole: the basal body (Pazour and Witman, 2003). Cilium biogenesis and The development of multicellular organisms requires function require a complex network of cilia-associated proteins the precisely coordinated regulation of an evolu- that serve, for example, to anchor the basal body to the cell tionarily conserved group of signaling pathways. membrane or to selectively allow protein entry and exit, thus Temporal and spatial control of these signaling cas- creating a distinct subcellular compartment (Gherman et al., cades is achieved through networks of regulatory 2006; Ishikawa and Marshall, 2011; Nachury et al., 2010; Pazour proteins, segregation of pathway components in and Witman, 2003; Pedersen et al., 2008; Reiter et al., 2012; Taschner et al., 2012). The ability to function as a separate specific subcellular compartments, or both. In verte- compartment appears key to the primary cilium acting as an brates, dysregulation of primary cilia function has environmental sensor and signaling hub (Berbari et al., 2009). been strongly linked to developmental signaling Cilia are critical for Sonic Hedgehog (Shh)/Hh signal transduc- defects, yet it remains unclear whether cilia tion, and potential roles in other developmental pathways are sequester pathway components to regulate their emerging (Berbari et al., 2009; Goetz and Anderson, 2010). The activation or cilia-associated proteins directly modu- Hh ligand binds to its receptor Patched (Ptc) to relieve Ptc inhibi- late developmental signaling events. To elucidate tion of Smoothened (Smo), which then activates the downstream this question, we conducted an RNAi-based screen transcription factor Ci (Gli in vertebrates). Ptc, Smo, and Gli all in Drosophila non-ciliated cells to test for cilium- localize to the cilium in vertebrates in a ligand-regulated manner, independent loss-of-function phenotypes of ciliary and ciliary mutants disrupt Hh signaling (Briscoe and The´ rond, proteins in developmental signaling pathways. 2013; Goetz et al., 2009). It is unclear whether cilia facilitate Hh signaling by providing a specialized subcellular compartment Our results show no effect on Hedgehog signaling. or whether (specific) ciliary components are directly required to In contrast, our screen identified several cilia- transduce the Hh signal. In contrast, the cilium has been sug- associated proteins as functioning in canonical gested to limit the response to Wnt signaling by affecting the sta- Wnt signaling. Further characterization of specific bility and localization of b-catenin/Armadillo (b-cat/Arm) (Oh and components of Intraflagellar Transport complex A Katsanis, 2013). When the Wnt/Wg ligand binds to its receptor uncovered a cilia-independent function in potenti- complex of Frizzled (Fz)/LRP5-6 (Arrow [Arr] in Drosophila) it in- ating Wnt signals by promoting b-catenin/Armadillo hibits the function of the b-cat destruction complex, allowing activity. b-cat accumulation and its nuclear translocation, as well as tran- scriptional activation via T-cell factor/lymphoid enhancer-bind- ing factor (TCF/LEF) transcription factors (Clevers and Nusse, INTRODUCTION 2012; MacDonald et al., 2009; Niehrs, 2012). Although roles for ciliary proteins in degrading b-cat and limiting its nuclear entry Signaling pathways that regulate embryonic development and have been reported (Corbit et al., 2008; Gerdes and Katsanis, adult homeostasis are highly conserved from Drosophila to hu- 2008), there are many contradicting conclusions from analyses mans. Many of these pathways were elucidated in Drosophila, of Wnt signaling in the context of ciliary mutants, ranging from in particular the Hedgehog (Hh), Wnt/Wingless (Wg), Notch (N), inactivation to overactivation of the pathway (Oh and Katsanis, and receptor tyrosine kinase (RTK) pathways, making the fly an 2013). Given the interest sparked by the primary cilium func- ideal organism to identify new pathway regulators. tioning in Hh and Wnt signaling, other signaling pathways, The primary cilium is an organelle involved in sensing the including N, RTK, and transforming growth factor b (TGF-b), extracellular environment, and it is required throughout develop- have been examined. However, a specific requirement for ment and for homeostasis in most eukaryotes. Cilia are microtu- cilia during signaling by each of these pathways remains to be Developmental Cell 34, 705–718, September 28, 2015 ª2015 Elsevier Inc. 705 confirmed (Christensen et al., 2012; Clement et al., 2013; Ezratty significant developmental defects and a secondary screen ex- et al., 2011; Leitch et al., 2014; Ten Dijke et al., 2012). amining specific molecular target genes to identify the res- The discovery that mutations in ciliary proteins can lead to pective signaling pathways affected by each KD (Figure 1; Fig- several genetic disorders, termed ciliopathies, has led to great ure S1; Table 1; Table S1). The Gal4-upstream activating interest in this cellular compartment. It remains unclear, how- sequence (UAS) system (Brand and Perrimon, 1993) was used ever, whether the affected ciliary proteins are directly required to drive RNAi expression (KD), and wherever possible, we for signal transduction or only to maintain the cilium as a func- used at least two independent non-overlapping RNAi lines to tioning compartment. Interestingly, different roles for ciliary eliminate false-positive off-target effects. In the wing, we used proteins in mitotic spindle orientation and immune synapse recy- engrailed (en)-Gal4 in the posterior compartment and nubbin cling that are independent of their function within the cilium have (nub)-Gal4 in the entire wing pouch. We additionally used recently been described (Delaval et al., 2011; Finetti et al., 2009; apterous (ap)-Gal4 in the thorax (Figures 1A–1G, S1A, and Sedmak and Wolfrum, 2010). The main barrier to understanding S1B and Table S1). KDs of 38 genes of the 62 tested genes how cilia-associated proteins could function independently of induced reproducible and specific phenotypes in the wing, tho- the cilium stems from the crucial role that most of these proteins rax, or both, and these were categorized according to their play in biogenesis and maintenance of the cilium; thus, it is diffi- appearance (Figures 1B–1G; Table S1; Figures S1A and S1B). cult to distinguish cilia-dependent and cilia-independent effects. These effects suggested cilia-independent functions for several To overcome this problem, we have used Drosophila as a model, cilia-associated proteins in the development of the wing, thorax, because here all cell types are non-ciliated, with the exception of or both. sensory neurons and sperm (Gogendeau and Basto, 2010). Con- To assess which signaling pathways were affected by candi- sequently, any phenotypes associated with the loss of cilia- date gene KDs, we first established control RNAi lines directed associated protein function should be due to cilia-independent to receptors of the respective developmental signaling path- functions. ways: Frizzled/Frizzled2 (Fz/Fz2-Wnt pathways), Notch (N We thus performed a two-step candidate RNAi-based screen pathway), Smo (Hh pathway), EGFR-RTK pathway, and Thick- in Drosophila, in vivo, to test for roles of cilia-associated proteins veins (Tkv-Dpp/TGF-b pathway) and compared these effects in developmental signaling pathways independent of their ciliary to the candidate KD phenotypes in adults (Figures 1B–1G; Ta- function. We first assayed adult phenotypes in the wing and ble S1; Figures S1A–S1C). Based on the adult wing and thorax thorax for developmental defects. The respective hits were phenotypes
Load more

Recommended publications
  • Ciliopathiesneuromuscularciliopathies Disorders Disorders Ciliopathiesciliopathies
    NeuromuscularCiliopathiesNeuromuscularCiliopathies Disorders Disorders CiliopathiesCiliopathies AboutAbout EGL EGL Genet Geneticsics EGLEGL Genetics Genetics specializes specializes in ingenetic genetic diagnostic diagnostic testing, testing, with with ne nearlyarly 50 50 years years of of clinical clinical experience experience and and board-certified board-certified labor laboratoryatory directorsdirectors and and genetic genetic counselors counselors reporting reporting out out cases. cases. EGL EGL Genet Geneticsics offers offers a combineda combined 1000 1000 molecular molecular genetics, genetics, biochemical biochemical genetics,genetics, and and cytogenetics cytogenetics tests tests under under one one roof roof and and custom custom test testinging for for all all medically medically relevant relevant genes, genes, for for domestic domestic andand international international clients. clients. EquallyEqually important important to to improving improving patient patient care care through through quality quality genetic genetic testing testing is is the the contribution contribution EGL EGL Genetics Genetics makes makes back back to to thethe scientific scientific and and medical medical communities. communities. EGL EGL Genetics Genetics is is one one of of only only a afew few clinical clinical diagnostic diagnostic laboratories laboratories to to openly openly share share data data withwith the the NCBI NCBI freely freely available available public public database database ClinVar ClinVar (>35,000 (>35,000 variants variants on on >1700 >1700 genes) genes) and and is isalso also the the only only laboratory laboratory with with a a frefree oen olinnlein dea dtabtaabsaes (eE m(EVmCVlaCslas)s,s f)e, afetuatruinrgin ag vaa vraiarniatn ctl acslasisfiscifiactiaotino sne saercahrc ahn adn rde rpeoprot rrte rqeuqeuset sint tinetrefarcfaec, ew, hwichhic fha cfailcitialiteatse rsa praidp id interactiveinteractive curation curation and and reporting reporting of of variants.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Ciliopathy-Associated Gene Cc2d2a Promotes Assembly of Subdistal Appendages on the Mother Centriole During Cilia Biogenesis
    ARTICLE Received 7 Apr 2014 | Accepted 23 May 2014 | Published 20 Jun 2014 DOI: 10.1038/ncomms5207 Ciliopathy-associated gene Cc2d2a promotes assembly of subdistal appendages on the mother centriole during cilia biogenesis Shobi Veleri1, Souparnika H. Manjunath1, Robert N. Fariss2, Helen May-Simera1, Matthew Brooks1, Trevor A. Foskett1, Chun Gao2, Teresa A. Longo1, Pinghu Liu3, Kunio Nagashima4, Rivka A. Rachel1, Tiansen Li1, Lijin Dong3 & Anand Swaroop1 The primary cilium originates from the mother centriole and participates in critical functions during organogenesis. Defects in cilia biogenesis or function lead to pleiotropic phenotypes. Mutations in centrosome-cilia gene CC2D2A result in Meckel and Joubert syndromes. Here we generate a Cc2d2a À / À mouse that recapitulates features of Meckel syndrome including embryonic lethality and multiorgan defects. Cilia are absent in Cc2d2a À / À embryonic node and other somatic tissues; disruption of cilia-dependent Shh signalling appears to underlie exencephaly in mutant embryos. The Cc2d2a À / À mouse embryonic fibroblasts (MEFs) lack cilia, although mother centrioles and pericentriolar pro- teins are detected. Odf2, associated with subdistal appendages, is absent and ninein is reduced in mutant MEFs. In Cc2d2a À / À MEFs, subdistal appendages are lacking or abnormal by transmission electron microscopy. Consistent with this, CC2D2A localizes to subdistal appendages by immuno-EM in wild-type cells. We conclude that CC2D2A is essential for the assembly of subdistal appendages, which anchor cytoplasmic microtubules and prime the mother centriole for axoneme biogenesis. 1 Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, NIH, Bethesda, Maryland 20892, USA. 2 Biological Imaging Core, National Eye Institute, NIH, Bethesda, Maryland 20892, USA.
    [Show full text]
  • Ciliopathies Gene Panel
    Ciliopathies Gene Panel Contact details Introduction Regional Genetics Service The ciliopathies are a heterogeneous group of conditions with considerable phenotypic overlap. Levels 4-6, Barclay House These inherited diseases are caused by defects in cilia; hair-like projections present on most 37 Queen Square cells, with roles in key human developmental processes via their motility and signalling functions. Ciliopathies are often lethal and multiple organ systems are affected. Ciliopathies are London, WC1N 3BH united in being genetically heterogeneous conditions and the different subtypes can share T +44 (0) 20 7762 6888 many clinical features, predominantly cystic kidney disease, but also retinal, respiratory, F +44 (0) 20 7813 8578 skeletal, hepatic and neurological defects in addition to metabolic defects, laterality defects and polydactyly. Their clinical variability can make ciliopathies hard to recognise, reflecting the ubiquity of cilia. Gene panels currently offer the best solution to tackling analysis of genetically Samples required heterogeneous conditions such as the ciliopathies. Ciliopathies affect approximately 1:2,000 5ml venous blood in plastic EDTA births. bottles (>1ml from neonates) Ciliopathies are generally inherited in an autosomal recessive manner, with some autosomal Prenatal testing must be arranged dominant and X-linked exceptions. in advance, through a Clinical Genetics department if possible. Referrals Amniotic fluid or CV samples Patients presenting with a ciliopathy; due to the phenotypic variability this could be a diverse set should be sent to Cytogenetics for of features. For guidance contact the laboratory or Dr Hannah Mitchison dissecting and culturing, with ([email protected]) / Prof Phil Beales ([email protected]) instructions to forward the sample to the Regional Molecular Genetics Referrals will be accepted from clinical geneticists and consultants in nephrology, metabolic, laboratory for analysis respiratory and retinal diseases.
    [Show full text]
  • Clinical Utility Gene Card For: Joubert Syndrome - Update 2013
    European Journal of Human Genetics (2013) 21, doi:10.1038/ejhg.2013.10 & 2013 Macmillan Publishers Limited All rights reserved 1018-4813/13 www.nature.com/ejhg CLINICAL UTILITY GENE CARD UPDATE Clinical utility gene card for: Joubert syndrome - update 2013 Enza Maria Valente*,1,2, Francesco Brancati1, Eugen Boltshauser3 and Bruno Dallapiccola4 European Journal of Human Genetics (2013) 21, doi:10.1038/ejhg.2013.10; published online 13 February 2013 Update to: European Journal of Human Genetics (2011) 19, doi:10.1038/ejhg.2011.49; published online 30 March 2011 1. DISEASE CHARACTERISTICS 1.6 Analytical methods 1.1 Name of the disease (synonyms) Direct sequencing of coding genomic regions and splice site junctions; Joubert syndrome (JS); Joubert-Boltshauser syndrome; Joubert syn- multiplex microsatellite analysis for detection of NPHP1 homozygous drome-related disorders (JSRD), including cerebellar vermis hypo/ deletion. Possibly, qPCR or targeted array-CGH for detection of aplasia, oligophrenia, congenital ataxia, ocular coloboma, and hepatic genomic rearrangements in other genes. fibrosis (COACH) syndrome; cerebellooculorenal, or cerebello-oculo- renal (COR) syndrome; Dekaban-Arima syndrome; Va´radi-Papp 1.7 Analytical validation syndrome or Orofaciodigital type VI (OFDVI) syndrome; Malta Direct sequencing of both DNA strands; verification of sequence and syndrome. qPCR results in an independent experiment. 1.2 OMIM# of the disease 1.8 Estimated frequency of the disease 213300, 243910, 216360, 277170. (incidence at birth-‘birth prevalence’-or population prevalence) No good population-based data on JSRD prevalence have been published. A likely underestimated frequency between 1/80 000 and 1.3 Name of the analysed genes or DNA/chromosome segments 1/100 000 live births is based on unpublished data.
    [Show full text]
  • REPORT CC2D2A, Encoding a Coiled-Coil and C2 Domain Protein, Causes Autosomal-Recessive Mental Retardation with Retinitis Pigmentosa
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector REPORT CC2D2A, Encoding A Coiled-Coil and C2 Domain Protein, Causes Autosomal-Recessive Mental Retardation with Retinitis Pigmentosa Abdul Noor,1 Christian Windpassinger,1,2 Megha Patel,1 Beata Stachowiak,1 Anna Mikhailov,1 Matloob Azam,3 Muhammad Irfan,4 Zahid Kamal Siddiqui,5 Farooq Naeem,6 Andrew D. Paterson,7 Muhammad Lutfullah,8 John B. Vincent,1,* and Muhammad Ayub9 Autosomal-recessive inheritance is believed to be relatively common in mental retardation (MR), although only four genes for nonsyn- dromic autosomal-recessive mental retardation (ARMR) have been reported. In this study, we ascertained a consanguineous Pakistani family with ARMR in four living individuals from three branches of the family, plus an additional affected individual later identified as a phenocopy. Retinitis pigmentosa was present in affected individuals, but no other features suggestive of a syndromic form of MR were found. We used Affymetrix 500K microarrays to perform homozygosity mapping and identified a homozygous and haploidentical region of 11.2 Mb on chromosome 4p15.33-p15.2. Linkage analysis across this region produced a maximum two-point LOD score of 3.59. We sequenced genes within the critical region and identified a homozygous splice-site mutation segregating in the family, within a coiled-coil and C2 domain-containing gene, CC2D2A. This mutation leads to the skipping of exon 19, resulting in a frameshift and a truncated protein lacking the C2 domain. Conservation analysis for CC2D2A suggests a functional domain near the C terminus as well as the C2 domain.
    [Show full text]
  • Ciliary Genes Arl13b, Ahi1 and Cc2d2a Differentially Modify Expression of Visual Acuity
    bioRxiv preprint doi: https://doi.org/10.1101/569822; this version posted March 6, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Ciliary Genes arl13b, ahi1 and cc2d2a Differentially Modify Expression of Visual Acuity 2 Phenotypes but do not Enhance Retinal Degeneration due to Mutation of cep290 in Zebrafish 3 4 Short title: Retinal degeneration in cep290 mutant zebrafish 5 6 7 Emma M. Lessieur1,2,4, Ping Song1,4, Gabrielle C. Nivar1, 8 Ellen M. Piccillo1, Joseph Fogerty1, Richard Rozic3, and Brian D. Perkins1,2 9 10 1Department of Ophthalmic Research, Cole Eye Institute, 11 Cleveland Clinic, Cleveland, OH 44195 United States 12 2Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, 13 Case Western Reserve University, Cleveland, OH 44195 United States 14 3Department of Biomedical Engineering, Lerner Research Institute, 15 Cleveland Clinic, Cleveland, OH 44195 United States 16 17 4These authors contributed equally to this work 18 Correspondence to: 19 Brian D. Perkins, Ph.D. 20 Department of Ophthalmic Research 21 Cleveland Clinic 22 9500 Euclid Ave 23 Building i3-156 24 Cleveland, OH 44195, USA 25 (Ph) 216-444-9683 26 (Fax) 216-445-3670 27 [email protected] 28 29 1 bioRxiv preprint doi: https://doi.org/10.1101/569822; this version posted March 6, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
    [Show full text]
  • Supplementary Information – Postema Et Al., the Genetics of Situs Inversus Totalis Without Primary Ciliary Dyskinesia
    1 Supplementary information – Postema et al., The genetics of situs inversus totalis without primary ciliary dyskinesia Table of Contents: Supplementary Methods 2 Supplementary Results 5 Supplementary References 6 Supplementary Tables and Figures Table S1. Subject characteristics 9 Table S2. Inbreeding coefficients per subject 10 Figure S1. Multidimensional scaling to capture overall genomic diversity 11 among the 30 study samples Table S3. Significantly enriched gene-sets under a recessive mutation model 12 Table S4. Broader list of candidate genes, and the sources that led to their 13 inclusion Table S5. Potential recessive and X-linked mutations in the unsolved cases 15 Table S6. Potential mutations in the unsolved cases, dominant model 22 2 1.0 Supplementary Methods 1.1 Participants Fifteen people with radiologically documented SIT, including nine without PCD and six with Kartagener syndrome, and 15 healthy controls matched for age, sex, education and handedness, were recruited from Ghent University Hospital and Middelheim Hospital Antwerp. Details about the recruitment and selection procedure have been described elsewhere (1). Briefly, among the 15 people with radiologically documented SIT, those who had symptoms reminiscent of PCD, or who were formally diagnosed with PCD according to their medical record, were categorized as having Kartagener syndrome. Those who had no reported symptoms or formal diagnosis of PCD were assigned to the non-PCD SIT group. Handedness was assessed using the Edinburgh Handedness Inventory (EHI) (2). Tables 1 and S1 give overviews of the participants and their characteristics. Note that one non-PCD SIT subject reported being forced to switch from left- to right-handedness in childhood, in which case five out of nine of the non-PCD SIT cases are naturally left-handed (Table 1, Table S1).
    [Show full text]
  • Cystic Kidney Diseases and During Vertebrate Gastrulation
    Pediatr Nephrol (2011) 26:1181–1195 DOI 10.1007/s00467-010-1697-5 REVIEW Cystic diseases of the kidney: ciliary dysfunction and cystogenic mechanisms Cecilia Gascue & Nicholas Katsanis & Jose L. Badano Received: 3 August 2010 /Revised: 15 September 2010 /Accepted: 15 October 2010 /Published online: 27 November 2010 # IPNA 2010 Abstract Ciliary dysfunction has emerged as a common Introduction factor underlying the pathogenesis of both syndromic and isolated kidney cystic disease, an observation that has Cystic diseases of the kidney are a significant contributor to contributed to the unification of human genetic disorders of renal malformations and a common cause of end stage renal the cilium, the ciliopathies. Such grouping is underscored disease (ESRD). This classification encompasses a number by two major observations: the fact that genes encoding of human disorders that range from conditions in which ciliary proteins can contribute causal and modifying cyst formation is either the sole or the main clinical mutations across several clinically discrete ciliopathies, manifestation, to pleiotropic syndromes where cyst forma- and the emerging realization that an understanding of the tion is but one of the observed pathologies, exhibits clinical pathology of one ciliopathy can provide valuable variable penetrance, and can sometimes be undetectable insight into the pathomechanism of renal cyst formation until later in life or upon necropsy (Table 1;[1]). elsewhere in the ciliopathy spectrum. In this review, we Importantly, although the different cystic kidney disorders discuss and attempt to stratify the different lines of are clinically discrete entities, an extensive body of data proposed cilia-driven mechanisms for cystogenesis, ranging fueled by a combination of mutation identification in from mechano- and chemo-sensation, to cell shape and humans and studies in animal models suggests a common polarization, to the transduction of a variety of signaling thread, where virtually all known renal cystic disease- cascades.
    [Show full text]
  • Ciliopathies
    T h e new england journal o f medicine Review article Mechanisms of Disease Robert S. Schwartz, M.D., Editor Ciliopathies Friedhelm Hildebrandt, M.D., Thomas Benzing, M.D., and Nicholas Katsanis, Ph.D. iverse developmental and degenerative single-gene disor- From the Howard Hughes Medical Insti- ders such as polycystic kidney disease, nephronophthisis, retinitis pigmen- tute and the Departments of Pediatrics and Human Genetics, University of Michi- tosa, the Bardet–Biedl syndrome, the Joubert syndrome, and the Meckel gan Health System, Ann Arbor (F.H.); the D Renal Division, Department of Medicine, syndrome may be categorized as ciliopathies — a recent concept that describes dis- eases characterized by dysfunction of a hairlike cellular organelle called the cilium. Center for Molecular Medicine, and Co- logne Cluster of Excellence in Cellular Most of the proteins that are altered in these single-gene disorders function at the Stress Responses in Aging-Associated Dis- level of the cilium–centrosome complex, which represents nature’s universal system eases, University of Cologne, Cologne, for cellular detection and management of external signals. Cilia are microtubule- Germany (T.B.); and the Center for Hu- man Disease Modeling and the Depart- based structures found on almost all vertebrate cells. They originate from a basal ments of Pediatrics and Cell Biology, body, a modified centrosome, which is the organelle that forms the spindle poles Duke University Medical Center, Durham, during mitosis. The important role that the cilium–centrosome complex plays in NC (N.K.). Address reprint requests to Dr. Hildebrandt at Howard Hughes Med- the normal function of most tissues appears to account for the involvement of mul- ical Institute, Departments of Pediatrics tiple organ systems in ciliopathies.
    [Show full text]
  • Ciliary Genes in Renal Cystic Diseases
    cells Review Ciliary Genes in Renal Cystic Diseases Anna Adamiok-Ostrowska * and Agnieszka Piekiełko-Witkowska * Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland * Correspondence: [email protected] (A.A.-O.); [email protected] (A.P.-W.); Tel.: +48-22-569-3810 (A.P.-W.) Received: 3 March 2020; Accepted: 5 April 2020; Published: 8 April 2020 Abstract: Cilia are microtubule-based organelles, protruding from the apical cell surface and anchoring to the cytoskeleton. Primary (nonmotile) cilia of the kidney act as mechanosensors of nephron cells, responding to fluid movements by triggering signal transduction. The impaired functioning of primary cilia leads to formation of cysts which in turn contribute to development of diverse renal diseases, including kidney ciliopathies and renal cancer. Here, we review current knowledge on the role of ciliary genes in kidney ciliopathies and renal cell carcinoma (RCC). Special focus is given on the impact of mutations and altered expression of ciliary genes (e.g., encoding polycystins, nephrocystins, Bardet-Biedl syndrome (BBS) proteins, ALS1, Oral-facial-digital syndrome 1 (OFD1) and others) in polycystic kidney disease and nephronophthisis, as well as rare genetic disorders, including syndromes of Joubert, Meckel-Gruber, Bardet-Biedl, Senior-Loken, Alström, Orofaciodigital syndrome type I and cranioectodermal dysplasia. We also show that RCC and classic kidney ciliopathies share commonly disturbed genes affecting cilia function, including VHL (von Hippel-Lindau tumor suppressor), PKD1 (polycystin 1, transient receptor potential channel interacting) and PKD2 (polycystin 2, transient receptor potential cation channel). Finally, we discuss the significance of ciliary genes as diagnostic and prognostic markers, as well as therapeutic targets in ciliopathies and cancer.
    [Show full text]
  • Clinical and Genetic Heterogeneity of Primary Ciliopathies (Review)
    INTERNATIONAL JOURNAL OF MOleCular meDICine 48: 176, 2021 Clinical and genetic heterogeneity of primary ciliopathies (Review) INA OFELIA FOCȘA1, MAGDALENA BUDIȘTEANU2‑4 and MIHAELA BĂLGRĂDEAN5,6 1Department of Medical Genetics, University of Medicine and Pharmacy ‘Carol Davila’, 021901 Bucharest; 2Department of Pediatric Neurology, ‘Prof. Dr. Alexandru Obregia’ Clinical Hospital of Psychiatry, 041914 Bucharest; 3Medical Genetic Laboratory, ‘Victor Babeș’ National Institute of Pathology, 050096 Bucharest; 4Department of Medical Genetics, Titu Maiorescu University, 040441 Bucharest; 5Department of Pediatrics and Pediatric Nephrology, Emergency Clinical Hospital for Children ‘Maria Skłodowska Curie’; 6Department of Pediatrics, University of Medicine and Pharmacy ‘Carol Davila’, 077120 Bucharest, Romania Received April 11, 2021; Accepted June 28, 2021 DOI: 10.3892/ijmm.2021.5009 Abstract. Ciliopathies comprise a group of complex disorders, by abnormal cilia biogenesis (1,2). The two main subcatego‑ with involvement of the majority of organs and systems. In ries, namely motile and immotile/primary ciliopathies, both total, >180 causal genes have been identified and, in addition involve disruption of the cilium, and also share several causal to Mendelian inheritance, oligogenicity, genetic modifications, genes (3‑5). However, clinically, they are quite different; epistatic interactions and retrotransposon insertions have all while motile ciliopathies (Kartagener syndrome and primary been described when defining the ciliopathic phenotype. It is ciliary dyskinesia) are characterized by pulmonary disease, remarkable how the structural and functional impairment of infertility, situs inversus or reversal of organ laterality (6), a single, minuscule organelle may lead to the pathogenesis of primary ciliopathies include a wide class of diseases that range highly pleiotropic diseases. Thus, combined efforts have been from organ‑specific disorders to pleiotropic syndromes with made to identify the genetic substratum and to determine the multiorgan involvement.
    [Show full text]