Skip to main content
SpringerLink
Log in

Ciliary subcompartments and cysto-proteins

  • Review Article
  • Published:
Anatomical Science International Aims and scope Submit manuscript

Abstract

Renal cystic diseases are conditions in which parts of or entire nephrons become enlarged and create fluid-filled cysts. These cysts occur in many genetic diseases. Most of the products of causative genes, termed cysto-proteins, are localized in cilia and/or centrioles. In addition, mutant mice lacking cilia develop renal cysts. Therefore, cilia are thought to have an important role in renal cystogenesis. The cilium is a tiny projection from the cell surface; however, it can be divided into several subcompartments. These subcompartments have specific roles. This review attempts to classify cysto-proteins based on their localization in ciliary subcompartments with the aim of defining relationships among them and of identifying their exact intraciliary functions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Bergmann C, Fliegauf M, Bruchle NO et al (2008) Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia. Am J Hum Genet 82:959–970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bhunia AK, Piontek K, Boletta A et al (2002) PKD1 induces p21(waf1) and regulation of the cell cycle via direct activation of the JAK-STAT signaling pathway in a process requiring PKD2. Cell 109:157–168

    Article  CAS  PubMed  Google Scholar 

  • Bialas NJ, Inglis PN, Li C et al (2009) Functional interactions between the ciliopathy-associated Meckel syndrome 1 (MKS1) protein and two novel MKS1-related (MKSR) proteins. J Cell Sci 122:611–624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bukanov NO, Smith LA, Klinger KW, Ledbetter SR, Ibraghimov-Beskrovnaya O (2006) Long-lasting arrest of murine polycystic kidney disease with CDK inhibitor roscovitine. Nature 444:949–952

    Article  CAS  PubMed  Google Scholar 

  • Chih B, Liu P, Chinn Y et al (2012) A ciliopathy complex at the transition zone protects the cilia as a privileged membrane domain. Nat Cell Biol 14:61–72

    Article  CAS  Google Scholar 

  • Cowley BD Jr, Smardo FL Jr, Grantham JJ, Calvet JP (1987) Elevated c-myc protooncogene expression in autosomal recessive polycystic kidney disease. Proc Natl Acad Sci USA 84:8394–8398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Czarnecki PG, Gabriel GC, Manning DK et al (2015) ANKS6 is the critical activator of NEK8 kinase in embryonic situs determination and organ patterning. Nat Commun 6:6023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Davenport JR, Watts AJ, Roper VC et al (2007) Disruption of intraflagellar transport in adult mice leads to obesity and slow-onset cystic kidney disease. Curr Biol 17:1586–1594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Downing KH, Sui H (2007) Structural insights into microtubule doublet interactions in axonemes. Curr Opin Struct Biol 17:253–259

    Article  CAS  PubMed  Google Scholar 

  • Fedeles SV, Gallagher AR, Somlo S (2014) Polycystin-1: a master regulator of intersecting cystic pathways. Trends Mol Med 20:251–260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fischer E, Legue E, Doyen A et al (2006) Defective planar cell polarity in polycystic kidney disease. Nat Genet 38:21–23

    Article  CAS  PubMed  Google Scholar 

  • Fukui H, Shiba D, Asakawa K, Kawakami K, Yokoyama T (2012) The ciliary protein Nek8/Nphp9 acts downstream of Inv/Nphp2 during pronephros morphogenesis and left-right establishment in zebrafish. FEBS Lett 586:2273–2279

    Article  CAS  PubMed  Google Scholar 

  • Galarreta CI, Grantham JJ, Forbes MS, Maser RL, Wallace DP, Chevalier RL (2014) Tubular obstruction leads to progressive proximal tubular injury and atubular glomeruli in polycystic kidney disease. Am J Pathol 184:1957–1966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garcia-Gonzalo FR, Corbit KC, Sirerol-Piquer MS et al (2011) A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition. Nat Genet 43:776–784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gj Pazour, SaJ Follit Ja, Jl Rosenbaum, Gb Witman (2002) Polycystin-2 localizes to kidney cilia and the ciliary level is elevated in orpk mice with polycystic kidney disease. Curr Biol 11:1341–1346

    Google Scholar 

  • Grantham JJ, Geiser JL, Evan AP (1987) Cyst formation and growth in autosomal dominant polycystic kidney disease. Kidney Int 31:1145–1152

    Article  CAS  PubMed  Google Scholar 

  • Hoff S, Halbritter J, Epting D et al (2013) ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3. Nat Genet 45:951–956

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kamura K, Kobayashi D, Uehara Y, Koshida S, Iijima N, Kudo A, Yokoyama T, Takeda H (2011) Pkd1l1 complexes with Pkd2 on motile cilia and functions to establish the left-right axis. Development 138:1121–1129

    Article  CAS  PubMed  Google Scholar 

  • Karner CM, Chirumamilla R, Aoki S, Igarashi P, Wallingford JB, Carroll TJ (2009) Wnt9b signaling regulates planar cell polarity and kidney tubule morphogenesis. Nat Genet 41:793–799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin F, Hiesberger T, Cordes K et al (2003) Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease. Proc Natl Acad Sci USA 100:5286–5291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu W, Shen Xiaohua, Pavlova Anna et al (2001) Comparison of Pkd1-targeted mutants reveals that loss of polycystin-1 causes cystogenesis and bone defects. Hum Mol Genet 10:2385–2396

    Article  CAS  PubMed  Google Scholar 

  • Ma M, Tian X, Igarashi P, Pazour GJ, Somlo S (2013) Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease. Nat Genet 45:1004–1012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Manning DK, Sergeev M, Van Heesbeen RG et al (2013) Loss of the ciliary kinase Nek8 causes left-right asymmetry defects. J Am Soc Nephrol 24:100–112

    Article  CAS  PubMed  Google Scholar 

  • Menezes LF, Cai Y, Nagasawa Y et al (2004) Polyductin, the PKHD1 gene product, comprises isoforms expressed in plasma membrane, primary cilium, and cytoplasm. Kidney Int 66:1345–1355

    Article  CAS  PubMed  Google Scholar 

  • Natoli TA, Gareski TC, Dackowski WR et al (2008) Pkd1 and Nek8 mutations affect cell–cell adhesion and cilia in cysts formed in kidney organ cultures. Am J Physiol Renal Physiol 294:F73–F83

    Article  CAS  PubMed  Google Scholar 

  • Nauli SM, Alenghat FJ, Luo Y et al (2003) Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet 33:129–137

    Article  CAS  PubMed  Google Scholar 

  • Nishio S, Tian X, Gallagher AR et al (2010) Loss of oriented cell division does not initiate cyst formation. J Am Soc Nephrol 21:295–302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nonaka S, Tanaka Y, Okada Y, Takeda S, Harada A, Kanai Y, Kido M, Hirokawa N (1998) Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell 95:829–837

    Article  CAS  PubMed  Google Scholar 

  • Okumura Y, Sugiyama N, Tanimura S et al (2009) ERK regulates renal cell proliferation and renal cyst expansion in inv mutant mice. Acta Histochem Cytochem 42:39–45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Omori S, Hida M, Fujita H et al (2006) Extracellular signal-regulated kinase inhibition slows disease progression in mice with polycystic kidney disease. J Am Soc Nephrol 17:1604–1614

    Article  CAS  PubMed  Google Scholar 

  • Pazour GJ, Dickert BL, Vucica Y et al (2000) Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene tg737, are required for assembly of cilia and flagella. J Cell Biol 151:709–718

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pedersen LB, Schroder JM, Satir P, Christensen ST (2012) The ciliary cytoskeleton. Compr Physiol 2:779–803

    PubMed  Google Scholar 

  • Pennekamp P, Karcher C, Fischer A, Schweickert A, Skryabin B, Horst J, Blum M, Dworniczak B (2002) The ion channel polycystin-2 Is required for left-right axis determination in mice. Curr Biol 12:938–943

    Article  CAS  PubMed  Google Scholar 

  • Piontek K, Menezes LF, Garcia-Gonzalez MA, Huso DL, Germino GG (2007) A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1. Nat Med 13:1490–1495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reiter JF, Blacque OE, Leroux MR (2012) The base of the cilium: roles for transition fibres and the transition zone in ciliary formation, maintenance and compartmentalization. EMBO Rep 13:608–618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rosenbaum JL, Child FM (1967) Flagellar regeneration in protozoan flagellates. J Cell Biol 34:345–364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saadi-Kheddouci S, Berrebi D, Romagnolo B et al (2001) Early development of polycystic kidney disease in transgenic mice expressing an activated mutant of the beta-catenin gene. Oncogene 20:5972–5981

    Article  CAS  PubMed  Google Scholar 

  • Saburi S, Hester I, Fischer E et al (2008) Loss of fat4 disrupts PCP signaling and oriented cell division and leads to cystic kidney disease. Nat Genet 40:1010–1015

    Article  CAS  PubMed  Google Scholar 

  • Sang L, Miller JJ, Corbit KC et al (2011) Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell 145:513–528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Satir P, Pedersen LB, Christensen ST (2010) The primary cilium at a glance. J Cell Sci 123:499–503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shiba D, Yokoyama T (2012) The ciliary transitional zone and nephrocystins. Differentiation 83:S91–S96

    Article  CAS  PubMed  Google Scholar 

  • Shiba D, Takamatsu T, Yokoyama T (2005) Primary cilia of inv/inv mouse renal epithelial cells sense physiological fluid flow: bending of primary cilia and Ca2+ influx. Cell Struct Funct 30:93–100

    Article  CAS  PubMed  Google Scholar 

  • Shiba D, Yamaoka Y, Hagiwara H, Takamatsu T, Hamada H, Yokoyama T (2009) Localization of Inv in a distinctive intraciliary compartment requires the C-terminal ninein-homolog-containing region. J Cell Sci 122:44–54

    Article  CAS  PubMed  Google Scholar 

  • Shiba D, Manning DK, Koga H, Beier DR, Yokoyama T (2010) Inv acts as a molecular anchor for Nphp3 and Nek8 in the proximal segment of primary cilia. Cytoskeleton (Hoboken) 67:112–119

    CAS  Google Scholar 

  • Shibazaki S, Yu Z, Nishio S et al (2008) Cyst formation and activation of the extracellular regulated kinase pathway after kidney specific inactivation of Pkd1. Hum Mol Genet 17:1505–1516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Simons M, Gloy J, Ganner A et al (2005) Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways. Nat Genet 37:537–543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sohara E, Luo Y, Zhang J, Manning DK, Beier DR, Zhou J (2008) Nek8 regulates the expression and localization of polycystin-1 and polycystin-2. J Am Soc Nephrol 19:469–476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sugiyama N, Yokoyama T (2006) Sustained cell proliferation of renal epithelial cells in mice with inv mutation. Genes Cells 11:1213–1224

    Article  CAS  PubMed  Google Scholar 

  • Sugiyama N, Tsukiyama T, Yamaguchi TP, Yokoyama T (2011) The canonical Wnt signaling pathway is not involved in renal cyst development in the kidneys of inv mutant mice. Kidney Int 79:957–965

    Article  CAS  PubMed  Google Scholar 

  • Torres VE (2008) Vasopressin antagonists in polycystic kidney disease. Semin Nephrol 28:306–317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Trudel M, Barisoni L, Lanoix J, D’agati V (1998) Polycystic kidney disease in SBM transgenic mice: role of c-myc in disease induction and progression. Am J Pathol 152:219–229

    CAS  PubMed  PubMed Central  Google Scholar 

  • Winey M, O’toole E (2014) Centriole structure. Philos Trans R Soc Lond B Biol Sci 369(1650):20130457. doi:10.1098/rstb.2013.0457

    Article  PubMed  PubMed Central  Google Scholar 

  • Yamaguchi T, Nagao S, Wallace DP et al (2003) Cyclic AMP activates B-Raf and ERK in cyst epithelial cells from autosomal-dominant polycystic kidneys. Kidney Int 63:1983–1994

    Article  CAS  PubMed  Google Scholar 

  • Yoder BK, Hou X, Guay-Woodford LM (2002) The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia. J Am Soc Nephrol 13:2508–2516

    Article  CAS  PubMed  Google Scholar 

  • Yokoyama T, Copeland NG, Jenkins NA, Montgomery CA, Elder FF, Overbeek PA (1993) Reversal of left-right asymmetry: a situs inversus mutation. Science 260:679–682

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Financial support of this study was provided by JSPS KAKENHI grant no. 26461235.

Author information

Authors and Affiliations

  1. Division of Developmental Biology, Department of Anatomy, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Hirokoji, Kawara-machi, Kamigyo-ku, Kyoto, 602-8566, Japan

    Takahiko Yokoyama

Authors
  1. Takahiko Yokoyama
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takahiko Yokoyama.

Ethics declarations

Conflict of interest

The author declares no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 237 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yokoyama, T. Ciliary subcompartments and cysto-proteins. Anat Sci Int 92, 207–214 (2017). https://doi.org/10.1007/s12565-015-0302-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12565-015-0302-1

Keywords

Search

Navigation