Photoreceptor Sensory Cilia and Inherited Retinal Degeneration

Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 664)


The outer segments of photoreceptor cells are specialized sensory cilia, and share many features with other primary and sensory cilia. Like other cilia, photoreceptor sensory cilium (PSC) comprises a membrane domain of outer segment and its cytoskeleton. We have recently identified the protein components of mouse PSCs, and found that the list of PSC proteins, called the PSC proteome, contains many novel cilia proteins. Studies have shown that many of the identified retinal degeneration disease genes encode proteins which are part of the PSC. Furthermore, mutations in genes encoding proteins expressed both in photoreceptors and other cilia result in systemic diseases, such as Usher syndrome, Bardet-Biedl syndrome (BBS), and Senior-Loken syndrome that involve retinal degeneration along with other disorders consequent to cilia dysfunction such as deafness and polycystic kidney disease. Based on these findings, we hypothesize that genes that encode proteins required for formation of PSCs are good candidate retinal degeneration disease genes. This chapter will summarize our studies on identifying novel PSC proteins from the PSC proteome. As an example of these studies, we demonstrated that tetratricopeptide the repeat domain 21B (TTC21B) protein is a novel PSC protein and is required for normal cilia formation in primary and photoreceptor sensory cilia.


Retinitis Pigmentosa Basal Body Outer Segment Primary Cilium Photoreceptor Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Allen RA (1965) Isolated cilia in inner retinal neurons and in retinal pigment epithelium. J Ultrastruct Res 12:730–747CrossRefPubMedGoogle Scholar
  2. Ansley SJ, Badano JL, Blacque OE et al (2003) Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome. Nature 425:628–633CrossRefPubMedGoogle Scholar
  3. Badano JL, Mitsuma N, Beales PL et al (2006) The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genomics Hum Genet 7:125–148CrossRefPubMedGoogle Scholar
  4. Berbari NF, Johnson AD, Lewis JS et al (2008) Identification of ciliary localization sequences within the third intracellular loop of G protein-coupled receptors. Mol Biol Cell 19:1540–1547CrossRefPubMedGoogle Scholar
  5. Breunig JJ, Sarkisian MR, Arellano JI et al (2008) Primary cilia regulate hippocampal neurogenesis by mediating sonic hedgehog signaling. Proc Natl Acad Sci USA 105:13127–13132CrossRefPubMedGoogle Scholar
  6. Cantagrel V, Silhavy JL, Bielas SL et al (2008) Mutations in the cilia gene ARL13B lead to the classical form of Joubert syndrome. Am J Hum Genet 83:170–179CrossRefPubMedGoogle Scholar
  7. Chang B, Khanna H, Hawes N et al (2006) In-frame deletion in a novel centrosomal/ciliary protein CEP290/NPHP6 perturbs its interaction with RPGR and results in early-onset retinal degeneration in the rd16 mouse. Hum Mol Genet 15:1847–1857CrossRefPubMedGoogle Scholar
  8. Christensen ST, Pedersen LB, Schneider L et al (2007) Sensory cilia and integration of signal transduction in human health and disease. Traffic 8:97–109CrossRefPubMedGoogle Scholar
  9. Daiger SP, Bowne SJ, Sullivan LS (2007) Perspective on genes and mutations causing retinitis pigmentosa. Arch Ophthalmol 125:151–158CrossRefPubMedGoogle Scholar
  10. Davis EE, Brueckner M, Katsanis N (2006) The emerging complexity of the vertebrate cilium: new functional roles for an ancient organelle. Dev Cell 11:9–19CrossRefPubMedGoogle Scholar
  11. De Robertis E (1956) Electron microscope observations on the submicroscopic organization of the retinal rods. J Biophys Biochem Cytol 2:319–330CrossRefGoogle Scholar
  12. den Hollander AI, Koenekoop RK, Yzer S et al (2006) Mutations in the CEP290 (NPHP6) gene are a frequent cause of leber congenital amaurosis. Am J Hum Genet 79:556–561CrossRefPubMedGoogle Scholar
  13. den Hollander AI, Koenekoop RK, Mohamed MD et al (2007) Mutations in LCA5, encoding the ciliary protein lebercilin, cause Leber congenital amaurosis. Nat Genet 39: 889–895CrossRefPubMedGoogle Scholar
  14. Fan Y, Esmail MA, Ansley SJ et al (2004) Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome. Nat Genet 36:989–993CrossRefPubMedGoogle Scholar
  15. Fliegauf M, Horvath J, von SC et al (2006) Nephrocystin specifically localizes to the transition zone of renal and respiratory cilia and photoreceptor connecting cilia. J Am Soc Nephrol 17:2424–2433CrossRefPubMedGoogle Scholar
  16. Gerdes JM, Liu Y, Zaghloul NA et al (2007) Disruption of the basal body compromises proteasomal function and perturbs intracellular Wnt response. Nat Genet 39:1350–1360CrossRefPubMedGoogle Scholar
  17. Gherman A, Davis EE, Katsanis N (2006) The ciliary proteome database: an integrated community resource for the genetic and functional dissection of cilia. Nat Genet 38:961–962CrossRefPubMedGoogle Scholar
  18. Giulietti A, Overbergh L, Valckx D et al (2001) An overview of real-time quantitative PCR: applications to quantify cytokine gene expression. Methods 25:386–401CrossRefPubMedGoogle Scholar
  19. Hartong DT, Berson EL, Dryja TP (2006) Retinitis pigmentosa. Lancet 368:1795–1809CrossRefPubMedGoogle Scholar
  20. Hildebrandt F, Zhou W (2007) Nephronophthisis-associated ciliopathies. J Am Soc Nephrol 18:1855–1871CrossRefPubMedGoogle Scholar
  21. Hong DH, Pawlyk BS, Shang J et al (2000) A retinitis pigmentosa GTPase regulator (RPGR)-deficient mouse model for X-linked retinitis pigmentosa (RP3). Proc Natl Acad Sci USA 97:3649–3654CrossRefPubMedGoogle Scholar
  22. Horst CJ, Johnson LV, Besharse JC (1990) Transmembrane assemblage of the photoreceptor connecting cilium and motile cilium transition zone contain a common immunologic epitope. Cell Motil Cytoskeleton 17:329–344CrossRefPubMedGoogle Scholar
  23. Jekely G, Arendt D (2006) Evolution of intraflagellar transport from coated vesicles and autogenous origin of the eukaryotic cilium. Bioessays 28:191–198CrossRefPubMedGoogle Scholar
  24. Kaplan MW, Iwata RT, Sears RC (1987) Lengths of immunolabeled ciliary microtubules in frog photoreceptor outer segments. Exp Eye Res 44:623–632CrossRefPubMedGoogle Scholar
  25. Liu Q, Zhou J, Daiger SP et al (2002) Identification and Subcellular Localization of the RP1 Protein in Human and Mouse Photoreceptors. Invest Ophthalmol Vis Sci 43:22–32PubMedGoogle Scholar
  26. Liu Q, Zuo J, Pierce EA (2004) The retinitis pigmentosa 1 protein is a photoreceptor microtubule-associated protein. J Neurosci 24:6427–6436CrossRefPubMedGoogle Scholar
  27. Liu Q, Tan G, Levenkova N et al (2007) The proteome of the mouse photoreceptor sensory cilium complex. Mol Cell Proteomics 6:1299–1317CrossRefPubMedGoogle Scholar
  28. Liu X, Vansant G, Udovichenko IP et al (1997) Myosin VIIa, the product of the Usher 1B syndrome gene, is concentrated in the connecting cilia of photoreceptor cells. Cell Motil Cytoskeleton 37:240–252CrossRefPubMedGoogle Scholar
  29. Maerker T, van WE, Overlack N et al (2008) A novel Usher protein network at the periciliary reloading point between molecular transport machineries in vertebrate photoreceptor cells. Hum Mol Genet 17:71–86CrossRefPubMedGoogle Scholar
  30. Maguire AM, Simonelli F, Pierce EA et al (2008) Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med 358:2240–2248CrossRefPubMedGoogle Scholar
  31. Matsuda T, Cepko CL (2004) Electroporation and RNA interference in the rodent retina in vivo and in vitro. Proc Natl Acad Sci USA 101:16–22CrossRefPubMedGoogle Scholar
  32. Matsusaka T (1974) Membrane Particles of the Connecting Cilium. J Ultrastruct Res 48:305–312CrossRefGoogle Scholar
  33. Otto EA, Loeys B, Khanna H et al (2005) Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin. Nat Genet 37:282–288CrossRefPubMedGoogle Scholar
  34. Pan J, Wang Q, Snell WJ (2005) Cilium-generated signaling and cilia-related disorders. Lab Invest 85:452–463CrossRefPubMedGoogle Scholar
  35. Reiners J, Marker T, Jurgens K et al (2005a) Photoreceptor expression of the Usher syndrome type 1 protein protocadherin 15 (USH1F) and its interaction with the scaffold protein harmonin (USH1C). Mol Vis 11:347–355PubMedGoogle Scholar
  36. Reiners J, van Wijk E, Marker T et al (2005b) Scaffold protein harmonin (USH1C) provides molecular links between Usher syndrome type 1 and type 2. Hum Mol Genet 14:3933–3943CrossRefPubMedGoogle Scholar
  37. RetNet (2008) RetNet Web site address.Google Scholar
  38. Roepman R, Letteboer SJ, Arts HH et al (2005) Interaction of nephrocystin-4 and RPGRIP1 is disrupted by nephronophthisis or Leber congenital amaurosis-associated mutations. Proc Natl Acad Sci USA 102:18520–18525CrossRefPubMedGoogle Scholar
  39. Sayer JA, Otto EA, O’Toole JF et al (2006) The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nat Genet 38:674–681CrossRefPubMedGoogle Scholar
  40. Simons M, Mlodzik M (2008) Planar cell polarity signaling: from fly development to human disease. Annu Rev Genet 42:517–540CrossRefPubMedGoogle Scholar
  41. Singla V, Reiter JF (2006) The primary cilium as the cell’s antenna: signaling at a sensory organelle. Science 313:629–633CrossRefPubMedGoogle Scholar
  42. Slough J, Cooney L, Brueckner M (2008) Monocilia in the embryonic mouse heart suggest a direct role for cilia in cardiac morphogenesis. Dev Dyn 237:2304–2314CrossRefPubMedGoogle Scholar
  43. Tran PV, Haycraft CJ, Besschetnova TY et al (2008) THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia. Nat Genet 40:403–410CrossRefPubMedGoogle Scholar
  44. Tucker RW, Pardee AB, Fujiwara K (1979) Centriole ciliation is related to quiescence and DNA synthesis in 3T3 cells. Cell 17:527–535CrossRefPubMedGoogle Scholar
  45. Valente EM, Silhavy JL, Brancati F et al (2006) Mutations in CEP290, which encodes a centrosomal protein, cause pleiotropic forms of Joubert syndrome. Nat Genet 38:623–625CrossRefPubMedGoogle Scholar
  46. Yang J, Gao J, Adamian M et al (2005) The ciliary rootlet maintains long-term stability of sensory cilia. Mol Cell Biol 25:4129–4137CrossRefPubMedGoogle Scholar
  47. Zhao Y, Hong DH, Pawlyk B et al (2003) The retinitis pigmentosa GTPase regulator (RPGR)- interacting protein: subserving RPGR function and participating in disk morphogenesis. Proc Natl Acad Sci USA 100:3965–3970CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.F.M. Kirby Center for Molecular OphthalmologyUniversity of Pennsylvania School of MedicinePhiladelphiaUSA

Personalised recommendations