The axoneme: the propulsive engine of spermatozoa and cilia and associated ciliopathies leading to infertility

Journal of Assisted Reproduction and Genetics

Volumn 33, Issue 2, 2016, Pages 141-156

  Linck, Richard W ^a   Chemes, Hector ^b   Albertini, David F ^c,d  

^a UNIVERSITY OF MINNESOTA   (United States)

^b Centro de Investigaciones Endocrinologicas   (Argentina)

^c UNIVERSITY OF KANSAS SCHOOL OF MEDICINE   (United States)

^d CENTER FOR HUMAN REPRODUCTION   (United States)

Author keywords

Basal body; Fibrous sheath; Intraflagellar transport; Microtubules; Outer dense fibers; Primary cilia

Indexed keywords

DYNEIN ADENOSINE TRIPHOSPHATASE;

AXONEME; DISEASE ASSOCIATION; GENETIC DISORDER; HUMAN; MALE FERTILITY; MALE INFERTILITY; MICROTUBULE; NONHUMAN; OSCILLATION; PRIORITY JOURNAL; REGULATORY MECHANISM; REVIEW; SPERMATOZOON; SPERMATOZOON MOTILITY; SPERMATOZOON TAIL; CILIUM; FLAGELLUM; GENETICS; INFERTILITY THERAPY; MALE; PATHOLOGY; ULTRASTRUCTURE;

AXONEME; CILIA; FLAGELLA; HUMANS; INFERTILITY, MALE; MALE; REPRODUCTIVE TECHNIQUES, ASSISTED; SPERMATOZOA;

EID: 84958752910     PISSN: 10580468     EISSN: 15737330     Source Type: Journal    
DOI: 10.1007/s10815-016-0652-1     Document Type: Review

References (165)

1. van Leeuwenhoek, A. http://lensonleeuwenhoek.net/.
2. Gray J. The movement of sea-urchin spermatozoa. J Exp Biol. 1955;32:775–801.
3. Vogl AW, Vaid KS, Guttman JA. The Sertoli cell cytoskeleton. Adv Exp Med Biol. 2008;636:186–211.
4. du Plessis SS, Kashou AH, Benjamin DJ, Yadav SP, Agarwal A. Proteomics: a subcellular look at spermatozoa. Reprod Biol Endocrinol. 2011;9:36.
5. Bedford JM. The epididymis re-visited: a personal view. Asian J Androl. 2015;17(5):693–8.
6. Ballowitz E. Untersuchungen uber die Struktur der Spermatozoen. Arch Mikr Anat. 1888;32:401–73.
7. Grigg GW, Hodge AJ. Electron microscopic studies of spermatozoa. Aust J Sci Res. 1949;2:271–86.
8. Manton I, Clarke B. An electron microscope study of the spermatozoid of sphagnum. J Exp Bot. 1952;3:265–74.
9. Fawcett DW, Porter KR. A study of the fine structure of ciliated epithelia. J Morphol. 1954;94:221–82.
10. Nicastro D, Schwartz C, Pierson J, Gaudette R, Porter ME, McIntosh JR. The molecular architecture of axonemes revealed by cryoelectron tomography. Science. 2006;313:944–8.
11. Nicastro D, Fu X, Heuser T, Tso A, Porter ME, Linck RW. Cryo-electron tomography reveals conserved features of doublet microtubules in flagella. Proc Natl Acad Sci U S A. 2011;108:E845–53.
12. Heuser T, Raytchev M, Krell J, Porter ME, Nicastro D. The dynein regulatory complex is the nexin link and a major regulatory node in cilia and flagella. J Cell Biol. 2009;187:921–33.
13. Lin J, Heuser T, Carbajal-Gonzalez BI, Song K, Nicastro D. The structural heterogeneity of radial spokes in cilia and flagella is conserved. Cytoskeleton. 2012;69:88–100.
14. Woodrum DT, Linck RW. Structural basis of motility in the microtubular axostyle: implications for cytoplasmic microtubule structure and function. J Cell Biol. 1980;87:404–14.
15. Linck RW, Stephens RE. Functional protofilament numbering of ciliary, flagellar, and centriolar microtubules. Cell Motil Cytoskeleton. 2007;64:489–95.
16. Linck R, Fu X, Lin J, Ouch C, Schefter A, Steffen W, et al. Insights into the structure and function of ciliary and flagellar doublet microtubules: tektins, Ca2 + −binding proteins, and stable protofilaments. J Biol Chem. 2014;289:17427–44.
17. Sleigh MA. Cilia and flagella. New York: Academic; 1974. p. 500.
18. Tam LW, Ranum PT, Lefebvre PA. CDKL5 regulates flagellar length and localizes to the base of the flagella in Chlamydomonas. Mol Biol Cell. 2013;24:588–600.
19. Satir P, Mitchell DR, Jekely G. How did the cilium evolve? Curr Top Dev Biol. 2008;85:63–82.
20. Baccetti B, Afzelius BA. The biology of the sperm cell. Monogr Dev Biol. 1976;1976:1–254.
21. Gibbons IR, Grimstone AV. On flagellar structure in certain flagellates. J Biophys Biochem Cytol. 1960;7:697–716.
22. Kuriyama R, Kanatani H. The centriolar complex isolated from starfish spermatozoa. J Cell Sci. 1981;49:33–49.
23. Guichard P, Hachet V, Majubu N, Neves A, Demurtas D, Olieric N, et al. Native architecture of the centriole proximal region reveals features underlying its 9-fold radial symmetry. Curr Biol. 2013;23:1620–8.
24. Stephens RE, Oleszko-Szuts S, Linck RW. Retention of ciliary ninefold structure after removal of microtubules. J Cell Sci. 1989;92(Pt 3):391–402.
25. Ostrowski LE, Blackburn K, Radde KM, Moyer MB, Schlatzer DM, Moseley A, et al. A proteomic analysis of human cilia: identification of novel components. Mol Cell Proteomics. 2002;1:451–65.
26. Gherman A, Davis EE, Katsanis N. The ciliary proteome database: an integrated community resource for the genetic and functional dissection of cilia. Nat Genet. 2006;38:961–2.
27. Fawcett DW. The mammalian spermatozoon. Dev Biol. 1975;44:394–436.
28. Fawcett DW. The cell. Philadelphia, London, Toronto: W.B. Saunders Company; 1981.
29. Linck RW, Olson GE, Langevin GL. Arrangement of tubulin subunits and microtubule-associated proteins in the central-pair microtubule apparatus of squid (Loligo pealei) sperm flagella. J Cell Biol. 1981;89:309–22.
30. Olson GE, Hamilton DW, Fawcett DW. Isolation and characterization of the fibrous sheath of rat epididymal spermatozoa. Biol Reprod. 1976;14:517–30.
31. Eddy EM, Toshimori K, O’Brien DA. Fibrous sheath of mammalian spermatozoa. Microsc Res Tech. 2003;61:103–15.
32. Brohmann H, Pinnecke S, Hoyer-Fender S. Identification and characterization of new cDNAs encoding outer dense fiber proteins of rat sperm. J Biol Chem. 1997;272:10327–32.
33. Lange BM, Gull K. A molecular marker for centriole maturation in the mammalian cell cycle. J Cell Biol. 1995;130:919–27.
34. Nakagawa Y, Yamane Y, Okanoue T, Tsukita S, Tsukita S. Outer dense fiber 2 is a widespread centrosome scaffold component preferentially associated with mother centrioles: its identification from isolated centrosomes. Mol Biol Cell. 2001;12:1687–97.
35. Tilney LG, Bryan J, Bush DJ, Fujiwara K, Mooseker MS, Murphy DB, et al. Microtubules: evidence for 13 protofilaments. J Cell Biol. 1973;59:267–75.
36. Mohri H. Amino-acid composition of “tubulin” constituting microtubules of sperm flagella. Nature. 1968;217:1053–4.
37. Luduena RF, Woodward DO. Isolation and partial characterization of alpha and beta-tubulin from outer doublets of sea-urchin sperm and microtubules of chick-embryo brain. Proc Natl Acad Sci U S A. 1973;70:3594–8.
38. Weisenberg RC. Microtubule formation in vitro in solutions containing low calcium concentrations. Science. 1972;177:1104–5.
39. Pierson GB, Burton PR, Himes RH. Alterations in number of protofilaments in microtubules assembled in vitro. J Cell Biol. 1978;76:223–8.
40. Ponstingl H, Krauhs E, Little M, Kempf T, Hofer-Warbinek R, Ade W. Amino acid sequence of a- and b-tubulins from pig brain. Cold Spring Harb Symp Quant Biol. 1982;46:191–7.
41. Li H, DeRosier DJ, Nicholson WV, Nogales E, Downing KH. Microtubule structure at 8 a resolution. Structure. 2002;10:1317–28.
42. Yu I, Garnham CP, Roll-Mecak A. Writing and reading the tubulin code. J Biol Chem. 2015;290:17163–72.
43. Allen C, Borisy GG. Structural polarity and directional growth of microtubules of Chlamydomonas flagella. J Mol Biol. 1974;90:381–402.
44. Fan J, Griffiths AD, Lockhart A, Cross RA, Amos LA. Microtubule minus ends can be labelled with a phage display antibody specific to alpha-tubulin. J Mol Biol. 1996;259:325–30.
45. Behnke O, Forer A. Evidence for four classes of microtubules in individual cells. J Cell Sci. 1967;2:169–92.
46. Amos L, Klug A. Arrangement of subunits in flagellar microtubules. J Cell Sci. 1974;14:523–49.
47. Linck RW, Amos LA. The hands of helical lattices in flagellar doublet microtubules. J Cell Sci. 1974;14:551–9.
48. Maheshwari A, Obbineni JM, Bui KH, Shibata K, Toyoshima YY, Ishikawa T. Alpha- and beta-tubulin lattice of the axonemal microtubule doublet and binding proteins revealed by single particle cryo-electron microscopy and tomography. Structure. 2015;23:1584–95.
49. Linck RW, Langevin GL. Reassembly of flagellar B (alpha beta) tubulin into singlet microtubules: consequences for cytoplasmic microtubule structure and assembly. J Cell Biol. 1981;89:323–37.
50. Caspary T, Larkins CE, Anderson KV. The graded response to sonic hedgehog depends on cilia architecture. Dev Cell. 2007;12:767–78.
51. Higginbotham H, Guo J, Yokota Y, Umberger NL, Su CY, Li J, et al. Arl13b-regulated cilia activities are essential for polarized radial glial scaffold formation. Nat Neurosci. 2013;16:1000–7.
52. Witman GB, Carlson K, Berliner J, Rosenbaum JL. Chlamydomonas flagella. I. Isolation and electrophoretic analysis of microtubules, matrix, membranes, and mastigonemes. J Cell Biol. 1972;54:507–39.
53. Linck RW, Langevin GL. Structure and chemical composition of insoluble filamentous components of sperm flagellar microtubules. J Cell Sci. 1982;58:1–22.
54. Steffen W, Linck RW. Evidence for tektins in centrioles and axonemal microtubules. Proc Natl Acad Sci U S A. 1988;85:2643–7.
55. Linck RW, Albertini DF, Kenney DM, Langevin GL. Tektin filaments: chemically unique filaments of sperm flagellar microtubules. Prog Clin Biol Res. 1982;80:127–32.
56. Yuan L, Liu JG, Hoog C. Rapid cDNA sequencing in combination with RNA expression studies in mice identifies a large number of male germ cell-specific sequence tags. Biol Reprod. 1995;52:131–8.
57. Norrander JM, Perrone CA, Amos LA, Linck RW. Structural comparison of tektins and evidence for their determination of complex spacings in flagellar microtubules. J Mol Biol. 1996;257:385–97.
58. Stephens RE, Lemieux NA. Tektins as structural determinants in basal bodies. Cell Motil Cytoskeleton. 1998;40:379–92.
59. Ikeda K, Brown JA, Yagi T, Norrander JM, Hirono M, Eccleston E, et al. Rib72, a conserved protein associated with the ribbon compartment of flagellar A-microtubules and potentially involved in the linkage between outer doublet microtubules. J Biol Chem. 2003;278:7725–34.
60. Stephens RE. Quantal tektin synthesis and ciliary length in sea-urchin embryos. J Cell Sci. 1989;92(Pt 3):403–13.
61. Norrander J, Larsson M, Stahl S, Hoog C, Linck R. Expression of ciliary tektins in brain and sensory development. J Neurosci Off J Soc Neurosci. 1998;18:8912–8.
62. Larsson M, Norrander J, Graslund S, Brundell E, Linck R, Stahl S, et al. The spatial and temporal expression of Tekt1, a mouse tektin C homologue, during spermatogenesis suggest that it is involved in the development of the sperm tail basal body and axoneme. Eur J Cell Biol. 2000;79:718–25.
63. Tanaka H, Iguchi N, Toyama Y, Kitamura K, Takahashi T, Kaseda K, et al. Mice deficient in the axonemal protein Tektin-t exhibit male infertility and immotile-cilium syndrome due to impaired inner arm dynein function. Mol Cell Biol. 2004;24:7958–64.
64. Roy A, Lin YN, Agno JE, DeMayo FJ, Matzuk MM. Absence of tektin 4 causes asthenozoospermia and subfertility in male mice. FASEB J Off Publ Fed Am Soc Exp Biol. 2007;21:1013–25.
65. Zuccarello D, Ferlin A, Garolla A, Pati MA, Moretti A, Cazzadore C, et al. A possible association of a human tektin-t gene mutation (A229V) with isolated non-syndromic asthenozoospermia: case report. Hum Reprod. 2008;23:996–1001.
66. Bhilawadikar R, Zaveri K, Mukadam L, Naik S, Kamble K, Modi D, et al. Levels of Tektin 2 and CatSper 2 in normozoospermic and oligoasthenozoospermic men and its association with motility, fertilization rate, embryo quality and pregnancy rate. J Assist Reprod Genet. 2013;30:513–23.
67. Cui Z, Sharma R, Agarwal A. Proteomic analysis of mature and immature ejaculated spermatozoa from fertile men. Asian J Androl. 2015. doi:10.4103/1008-682X.164924.
68. Zhang S, Zhang J, Xianping D, Zhang S, Chen H, Jing Y. Asssociation of polymorphisms in tektin-t gene with idiopathic asthernozoospermia in Sichuan, China. J Assist Reprod Genet. 2015. doi:10.1007/s10815-015-0617-9.
69. Hashemitabar M, Sabbagh S, Orazizadeh M, Ghadiri A, Bahmanzadeh M. A proteomic analysis on human sperm tail: comparison between normozoospermia and asthenozoospermia. J Assist Reprod Genet. 2015;32:853–63.
70. Iguchi N, Tanaka H, Nakamura Y, Nozaki M, Fujiwara T, Nishimune Y. Cloning and characterization of the human tektin-t gene. Mol Hum Reprod. 2002;8:525–30.
71. Wolkowicz MJ, Naaby-Hansen S, Gamble AR, Reddi PP, Flickinger CJ, Herr JC. Tektin B1 demonstrates flagellar localization in human sperm. Biol Reprod. 2002;66:241–50.
72. Matsuyama T, Honda Y, Doiguchi M, Iida H. Molecular cloning of a new member of TEKTIN family, Tektin4, located to the flagella of rat spermatozoa. Mol Reprod Dev. 2005;72:120–8.
73. Gibbons IR. Chemical dissection of cilia. Arch Biol. 1965;76:317–52.
74. Afzelius B. Electron microscopy of the sperm tail; results obtained with a new fixative. J Biophys Biochem Cytol. 1959;5:269–78.
75. Sha YW, Ding L, Li P. Management of primary ciliary dyskinesia/Kartagener’s syndrome in infertile male patients and current progress in defining the underlying genetic mechanism. Asian J Androl. 2014;16:101–6.
76. Praveen K, Davis EE, Katsanis N. Unique among ciliopathies: primary Ciliary dyskinesia, a motile cilia disorder. F1000prime Rep. 2015;7:36.
77. Werner C, Onnebrink JG, Omran H. Diagnosis and management of primary ciliary dyskinesia. Cilia. 2015;4:2.
78. Ben Khelifa M, Coutton C, Zouari R, Karaouzene T, Rendu J, Bidart M, et al. Mutations in DNAH1, which encodes an inner arm heavy chain dynein, lead to male infertility from multiple morphological abnormalities of the sperm flagella. Am J Hum Genet. 2014;94:95–104.
79. King SM, and Kamiya R. Axonemal dyneins: assembly, structure and force generation. The Chlamydomonas Sourcebook. 2nd ed. 3:131–208, 2009.
80. Hom EF, Witman GB, Harris EH, Dutcher SK, Kamiya R, Mitchell DR, et al. A unified taxonomy for ciliary dyneins. Cytoskeleton. 2011;68:555–65.
81. Satir P. Studies on cilia. 3. Further studies on the cilium tip and a “sliding filament” model of ciliary motility. J Cell Biol. 1968;39:77–94.
82. Gibbons BH, Gibbons IR. Flagellar movement and adenosine triphosphatase activity in sea urchin sperm extracted with triton X-100. J Cell Biol. 1972;54:75–97.
83. Gibbons BH, Gibbons IR. The effect of partial extraction of dynein arms on the movement of reactivated sea-urchin sperm. J Cell Sci. 1973;13:337–57.
84. Summers KE, Gibbons IR. Adenosine triphosphate-induced sliding of tubules in trypsin-treated flagella of sea-urchin sperm. Proc Natl Acad Sci U S A. 1971;68:3092–6.
85. Sale WS, Satir P. Direction of active sliding of microtubules in tetrahymena cilia. Proc Natl Acad Sci U S A. 1977;74:2045–9.
86. Brokaw CJ. Direct measurements of sliding between outer doublet microtubules in swimming sperm flagella. Science. 1989;243:1593–6.
87. Burgess SA, Walker ML, Sakakibara H, Knight PJ, Oiwa K. Dynein structure and power stroke. Nature. 2003;421:715–8.
88. Lin J, Okada K, Raytchev M, Smith MC, Nicastro D. Structural mechanism of the dynein power stroke. Nat Cell Biol. 2014;16:479–85.
89. Piperno G, Mead K, Shestak W. The inner dynein arms I2 interact with a “dynein regulatory complex” in Chlamydomonas flagella. J Cell Biol. 1992;118:1455–63.
90. Wirschell M, Olbrich H, Werner C, Tritschler D, Bower R, Sale WS, et al. The nexin-dynein regulatory complex subunit DRC1 is essential for motile cilia function in algae and humans. Nat Genet. 2013;45:262–8.
91. Brokaw CJ, Kamiya R. Bending patterns of Chlamydomonas flagella: IV. Mutants with defects in inner and outer dynein arms indicate differences in dynein arm function. Cell Motil Cytoskeleton. 1987;8:68–75.
92. Lindemann CB, Mitchell DR. Evidence for axonemal distortion during the flagellar beat of Chlamydomonas. Cell Motil Cytoskeleton. 2007;64:580–9.
93. Lindemann CB, Lesich KA. The geometric clutch at 20: stripping gears or gaining traction? Reproduction. 2015;150:R45–53.
94. Lin J, Tritschler D, Song K, Barber CF, Cobb JS, Porter ME, et al. Building blocks of the nexin-dynein regulatory complex in Chlamydomonas flagella. J Biol Chem. 2011;286:29175–91.
95. Hopkins JM. Subsidiary components of the flagella of Chlamydomonas reinhardii. J Cell Sci. 1970;7:823–39.
96. Warner FD, Satir P. The structural basis of ciliary bend formation. Radial spoke positional changes accompanying microtubule sliding. J Cell Biol. 1974;63:35–63.
97. Olson GE, Linck RW. Observations of the structural components of flagellar axonemes and central pair microtubules from rat sperm. J Ultrastruct Res. 1977;61:21–43.
98. Piperno G, Huang B, Luck DJ. Two-dimensional analysis of flagellar proteins from wild-type and paralyzed mutants of Chlamydomonas reinhardtii. Proc Natl Acad Sci U S A. 1977;74:1600–4.
99. Huang B, Piperno G, Ramanis Z, Luck DJ. Radial spokes of Chlamydomonas flagella: genetic analysis of assembly and function. J Cell Biol. 1981;88:80–8.
100. Smith EF, Yang P. The radial spokes and central apparatus: mechano-chemical transducers that regulate flagellar motility. Cell Motil Cytoskeleton. 2004;57:8–17.
101. Dymek EE, Smith EF. A conserved CaM- and radial spoke associated complex mediates regulation of flagellar dynein activity. J Cell Biol. 2007;179:515–26.
102. Gokhale A, Wirschell M, Sale WS. Regulation of dynein-driven microtubule sliding by the axonemal protein kinase CK1 in Chlamydomonas flagella. J Cell Biol. 2009;186:817–24.
103. Yang P, and Smith EF. Radial spokes of Chlamydomonas flagella: genetic analysis of assembly and function. The Chlamydomonas Sourcebook. 2nd edn. Cell Motil Behav. 2009;3: 209–234.
104. Oda T, Yanagisawa H, Yagi T, Kikkawa M. Mechanosignaling between central apparatus and radial spokes controls axonemal dynein activity. J Cell Biol. 2014;204:807–19.
105. James SW, Silflow CD, Stroom P, Lefebvre PA. A mutation in the alpha 1-tubulin gene of Chlamydomonas reinhardtii confers resistance to anti-microtubule herbicides. J Cell Sci. 1993;106(Pt 1):209–18.
106. Oda T, Yanagisawa H, Kamiya R, Kikkawa M. A molecular ruler determines the repeat length in eukaryotic cilia and flagella. Science. 2014;346:857–60.
107. Henley C, Costello DP, Thomas MB, Newton WD. The “9 + 1” pattern of microtubules in spermatozoa of mesostoma (platyhelminthes, turbellaria). Proc Natl Acad Sci U S A. 1969;64:849–56.
108. Carbajal-Gonzalez BI, Heuser T, Fu X, Lin J, Smith BW, Mitchell DR, et al. Conserved structural motifs in the central pair complex of eukaryotic flagella. Cytoskeleton. 2013;70:101–20.
109. Omoto CK, Kung C. Rotation and twist of the central-pair microtubules in the cilia of paramecium. J Cell Biol. 1980;87:33–46.
110. Tamm SL, Tamm S. Ciliary reversal without rotation of axonemal structures in ctenophore comb plates. J Cell Biol. 1981;89:495–509.
111. Woolley DM, Vernon GG. A study of helical and planar waves on sea urchin sperm flagella, with a theory of how they are generated. J Exp Biol. 2001;204:1333–45.
112. Hirokawa N, Tanaka Y, Okada Y, Takeda S. Nodal flow and the generation of left-right asymmetry. Cell. 2006;125:33–45.
113. Wilson LG, Carter LM, Reece SE. High-speed holographic microscopy of malaria parasites reveals ambidextrous flagellar waveforms. Proc Natl Acad Sci U S A. 2013;110:18769–74.
114. Brokaw CJ. Computer simulation of flagellar movement X: doublet pair splitting and bend propagation modeled using stochastic dynein kinetics. Cytoskeleton. 2014;71:273–84.
115. Pazour GJ, Sineshchekov OA, Witman GB. Mutational analysis of the phototransduction pathway of Chlamydomonas reinhardtii. J Cell Biol. 1995;131:427–40.
116. Kaupp UB. 100 years of sperm chemotaxis. J Gen Physiol. 2012;140:583–6.
117. Lesich KA, dePinho TG, Dionne BJ, Lindemann CB. The effects of Ca2+ and ADP on dynein switching during the beat cycle of reactivated bull sperm models. Cytoskeleton. 2014;71:611–27.
118. Perez-Cerezales S, Boryshpolets S, Eisenbach M. Behavioral mechanisms of mammalian sperm guidance. Asian J Androl. 2015;17:628–32.
119. Seifert R, Flick M, Bonigk W, Alvarez L, Trotschel C, Poetsch A, et al. The CatSper channel controls chemosensation in sea urchin sperm. EMBO J. 2015;34:379–92.
120. Kozminsky KG, Johnson KA, Forscher P, Rosenbaum JL. A motility in the eukaryotic flagellum unrelated to flagellar beating. Proc Natl Acad Sci U S A. 1993;90:5519–23.
121. Rosenbaum JL, Witman GB. Intraflagellar transport. Nat Rev Mol Cell Biol. 2002;3:813–25.
122. Berbari NF, O’Connor AK, Haycraft CJ, Yoder BK. The primary cilium as a complex signaling center. Curr Biol. 2009;19:R526–35.
123. Engel BD, Ishikawa H, Wemmer KA, Geimer S, Wakabayashi K, Hirono M, et al. The role of retrograde intraflagellar transport in flagellar assembly, maintenance, and function. J Cell Biol. 2012;199:151–67.
124. Stephens RE. Synthesis and turnover of embryonic sea urchin ciliary proteins during selective inhibition of tubulin synthesis and assembly. Mol Biol Cell. 1997;8:2187–98.
125. Stephens RE. Ciliogenesis, ciliary function, and selective isolation. ACS Chem Biol. 2008;3:84–6.
126. Watnick TJ, Jin Y, Matunis E, Kernan MJ, Montell C. A flagellar polycystin-2 homolog required for male fertility in drosophila. Curr Biol. 2003;13:2179–84.
127. Loktev AV, Zhang Q, Beck JS, Searby CC, Scheetz TE, Bazan JF, et al. A BBSome subunit links ciliogenesis, microtubule stability, and acetylation. Dev Cell. 2008;15:854–65.
128. Afzelius BA, Eliasson R, Johnsen O, Lindholmer C. Lack of dynein arms in immotile human spermatozoa. J Cell Biol. 1975;66:225–32.
129. Pedersen H, Rebbe H. Absence of arms in the axoneme of immobile human spermatozoa. Biol Reprod. 1975;12:541–4.
130. Chemes HE, Brugo S, Zanchetti F, Carrere C, Lavieri JC. Dysplasia of the fibrous sheath: an ultrastructural defect of human spermatozoa associated with sperm immotility and primary sterility. Fertil Steril. 1987;48:664–9.
131. Chemes HE, Olmedo SB, Carrere C, Oses R, Carizza C, Leisner M, et al. Ultrastructual pathology of the sperm flagellum. Association between flagellar pathology and fertility prognosis in severely asthenozoospermic men. Hum Reprod. 1998;13:2521–6.
132. Chemes E, Rawe VY. Origin, characterization and fertility potential of abnormal sperm phenotypes in infertile men. Hum Reprod Update. 2003;9:405–28.
133. Chemes HE, Rawe VY. The making of abnormal spermatozoa: cellular and molecular mechanisms underlying pathological spermiogenesis. Cell Tissue Res. 2010;341:349–57.
134. Afzelius BA. Situs inversus and ciliary abnormalities. What is the connection? Int J Dev Biol. 1995;39:839–44.
135. Nonaka S, Tanaka Y, Okada Y, Takeda S, Harada A, Kanai Y, et al. Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell. 1998;95:829–37.
136. Eliasson R, Mossberg B, Camner P, Afzelius BA. The immotile cilia syndrome: a congenital ciliary abnormality as an etiologic factor in chronic airway infections and male sterility. N Engl J Med. 1976;297:1–6.
137. Sleigh MA. Primary ciliary dyskinesia. Lancet. 1981;318:476.
138. Rossman CM, Forrest JB, Lee RM, Newhouse AF, Newhouse MT. The dyskinetic cilia syndrome; abnormal ciliary motility in association with abnormal ciliary ultrastructure. Chest. 1981;80:860–5.
139. Alberts B, Johnson A, Lewis J, Morgan D, Raff M, Roberts K, et al. Molecular biology of the cell. 6th ed. New York, NY: Garland Science; 2015. p. 1342.
140. Afzelius BA, Eliasson R. Flagellar mutants in man: on the heterogeneity of the immotile-cilia syndrome. J Ultrastruct Res. 1979;69:43–52.
141. Sturgess JM, Chao J, Wong J, Aspin N, Turner JA. Cilia with defective radial spokes: a cause of human respiratory disease. N Engl J Med. 1979;300:53–6.
142. Sturgess JM, Chao J, Turner JA. Transposition of ciliary microtubules: another cause of impaired ciliary motility. N Engl J Med. 1980;303:318–22.
143. de Santi MM, Gardi C, Barlocco G, Canciani M, Mastella G, Lungarella G. Cilia-lacking respiratory cells in ciliary aplasia. Biol Cell Auspices Eur Cell Biol Organ. 1988;64:67–70.
144. Wartchow EP, Jaffe R, Mierau GW. Ciliary inclusion disease: report of a new primary ciliary dyskinesia variant. Pediatr Dev Pathol. 2014;17:465–9.
145. Lindemann CB. Functional significance of the outer dense fibers of mammalian sperm examined by computer simulations with the geometric clutch model. Cell Motil Cytoskeleton. 1996;34:258–70.
146. Tateishi K, Yamazaki Y, Nishida T, Watanabe S, Kunimoto K, Ishikawa H, et al. Two appendages homologous between basal bodies and centrioles are formed using distinct Odf2 domains. J Cell Biol. 2013;203:417–25.
147. Ross A, Christie S, Edmond P. Ultrastructural tail defects in the spermatozoa from two men attending a subfertility clinic. J Reprod Fertil. 1973;32:243–51.
148. Bisson JP, Leonard C, David G. Familial character of some morphological abnormalities of spermatozoa (author’s transl). Arch Anat Cytol Pathol. 1979;27:230–3.
149. McClure RD, Brawer J, Robaire B. Ultrastructure of immotile spermatozoa in an infertile male: a spectrum of structural defects. Fertil Steril. 1983;40:395–9.
150. Escalier D, David G. Pathology of the cytoskeleton of the human sperm flagellum: axonemal and peri-axonemal anomalies. Biol Cell Auspices Eur Cell Biol Organ. 1984;50:37–52.
151. Baccetti B, Collodel G, Estenoz M, Manca D, Moretti E, Piomboni P. Gene deletions in an infertile man with sperm fibrous sheath dysplasia. Hum Reprod. 2005;20:2790–4.
152. Coutton C, Escoffier J, Martinez G, Arnoult C, Ray PF. Teratozoospermia: spotlight on the main genetic actors in the human. Hum Reprod Update. 2015;21:455–85.
153. Praetorius HA, Spring KR. Bending the MDCK cell primary cilium increases intracellular calcium. J Membr Biol. 2001;184:71–9.
154. Li X, Luo Y, Starremans PG, McNamara CA, Pei Y, Zhou J. Polycystin-1 and polycystin-2 regulate the cell cycle through the helix-loop-helix inhibitor Id2. Nat Cell Biol. 2005;7:1202–12.
155. Okada H, Fujioka H, Tatsumi N, Fujisawa M, Gohji K, Arakawa S, et al. Assisted reproduction for infertile patients with 9 + 0 immotile spermatozoa associated with autosomal dominant polycystic kidney disease. Hum Reprod. 1999;14:110–3.
156. Kanagarajah P, Ayyathurai R, Lynne CM. Male infertility and adult polycystic kidney disease--revisited: case report and current literature review. Andrologia. 2012;44 Suppl 1:838–41.
157. Nie X, Arend LJ. Pkd1 is required for male reproductive tract development. Mech Dev. 2013;130:567–76.
158. Nie X, Arend LJ. Novel roles of Pkd2 in male reproductive system development. Differentiation. 2014;87:161–71.
159. Brunner S, Colman D, Travis AJ, Luhmann UF, Shi W, Feil S, et al. Overexpression of RPGR leads to male infertility in mice due to defects in flagellar assembly. Biol Reprod. 2008;79:608–17.
160. Afzelius BA. Cilia-related diseases. J Pathol. 2004;204:470–7.
161. Fliegauf M, Benzing T, Omran H. When cilia go bad: cilia defects and ciliopathies. Nat Rev Mol Cell Biol. 2007;8:880–93.
162. Magloire H, Couble ML, Romeas A, Bleicher F. Odontoblast primary cilia: facts and hypotheses. Cell Biol Int. 2004;28:93–9.
163. D’Angelo A, Franco B. The dynamic cilium in human diseases. PathoGenetics. 2009;2:3.
164. Tobin JL, Beales PL. The nonmotile ciliopathies. Genet Med Off J Am Coll Med Genet. 2009;11:386–402.
165. Bangs FK, Schrode N, Hadjantonakis AK, Anderson KV. Lineage specificity of primary cilia in the mouse embryo. Nat Cell Biol. 2015;17:113–22.