Immunoglobulin-Like Domains Have an Evolutionarily Conserved Role During Gamete Fusion in C. elegans and Mouse

  • Tatsuya Tajima
  • Hitoshi NishimuraEmail author


The spe-9 class genes are predominantly or exclusively expressed in the C. elegans male germline and play critical roles during gamete fusion. However, it is a challenge to identify mammalian orthologs that exhibit similar functions to those of the spe-9 class, since reproductive genes evolve much faster than somatic genes. In the mouse, Izumo1 gene encodes a sperm-specific transmembrane (TM) protein with the immunoglobulin (Ig)-like domain that indispensably acts during gamete fusion. The C. elegans gene spe-45 was recently identified by forward and reverse genetic approaches. It shows male germline-enriched expression and encodes an Ig-like TM protein like IZUMO1. Worms lacking spe-45 produce otherwise normal spermatozoa that are incapable of fusing with oocytes. Thus, spe-45 is a new member of the spe-9 class, and the phenotype of spe-45 mutant worms is essentially the same as that of Izumo1-knockout mice. Moreover, the Ig-like domains of SPE-45 and IZUMO1 possess similar roles to each other during gamete fusion. This indicates that C. elegans spe-45 is functionally equivalent to mouse Izumo1 and that their roles during gamete fusion have been conserved for ~1 billion years. Intriguingly, diverged organisms also have TM proteins with Ig-like domains that are involved during gamete interactions. This suggests the evolutionarily conserved roles of the Ig-like domains during fertilization, which are presumably related to associating with cis- and/or trans-partners.


C. elegans Mouse Fertilization Gamete fusion Sperm spe-45 Izumo1 Immunoglobulin-like domain Transmembrane protein 


  1. Argon Y, Ward S (1980) Caenorhabditis elegans fertilization-defective mutants with abnormal sperm. Genetics 96(2):413–433PubMedPubMedCentralGoogle Scholar
  2. Aydin H, Sultana A, Li S, Thavalingam A, Lee JE (2016) Molecular architecture of the human sperm IZUMO1 and egg JUNO fertilization complex. Nature 534(7608):562–565. Scholar
  3. Beech DJ, Bahnasi YM, Dedman AM, Al-Shawaf E (2009) TRPC channel lipid specificity and mechanisms of lipid regulation. Cell Calcium 45(6):583–588CrossRefPubMedCentralPubMedGoogle Scholar
  4. Bianchi E, Doe B, Goulding D, Wright GJ (2014) Juno is the egg Izumo receptor and is essential for mammalian fertilization. Nature 508(7497):483–487. Scholar
  5. Borden KL (2000) RING domains: master builders of molecular scaffolds? J Mol Biol 295(5):1103–1112CrossRefPubMedCentralPubMedGoogle Scholar
  6. Brenner S (1974) The genetics of Caenorhabditis elegans. Genetics 77(1):71–94PubMedPubMedCentralGoogle Scholar
  7. Chatterjee I, Richmond A, Putiri E, Shakes DC, Singson A (2005) The Caenorhabditis elegans spe-38 gene encodes a novel four-pass integral membrane protein required for sperm function at fertilization. Development 132:2795–2808CrossRefPubMedCentralPubMedGoogle Scholar
  8. Cordle J, Johnson S, Tay JZ, Roversi P, Wilkin MB, de Madrid BH, Shimizu H, Jensen S, Whiteman P, Jin B, Redfield C, Baron M, Lea SM, Handford PA (2008) A conserved face of the Jagged/Serrate DSL domain is involved in Notch trans-activation and cis-inhibition. Nat Struct Mol Biol 15(8):849–857CrossRefPubMedCentralPubMedGoogle Scholar
  9. Doniach T, Hodgkin J (1984) A sex-determining gene, fem-1, required for both male and hermaphrodite development in Caenorhabditis elegans. Dev Biol 106(1):223–235CrossRefPubMedCentralPubMedGoogle Scholar
  10. Ferris PJ, Woessner JP, Goodenough UW (1996) A sex recognition glycoprotein is encoded by the plus mating-type gene fus1 of Chlamydomonas reinhardtii. Mol Biol Cell 7(8):1235–1248CrossRefPubMedCentralPubMedGoogle Scholar
  11. Florman HM, Fissore RA (2014) Fertilization in mammals. In: Plant TM, Zeleznik AJ (eds) Knobil and Neill’s physiology of reproduction, 4th edn. Elsevier Academic Press, Amsterdam (Netherlands), pp 149–196Google Scholar
  12. Grayson P (2015) Izumo1 and Juno: the evolutionary origins and coevolution of essential sperm-egg binding partners. R Soc Open Sci 2(12):150296. Scholar
  13. Grzmil P, Kim Y, Shamsadin R, Neesen J, Adham IM, Heinlein UA, Schwarzer UJ, Engel W (2001) Human cyritestin genes (CYRN1 and CYRN2) are non-functional. Biochem J 357(Pt 2):551–556CrossRefPubMedCentralPubMedGoogle Scholar
  14. Haerty W, Jagadeeshan S, Kulathinal RJ, Wong A, Ravi Ram K, Sirot LK, Levesque L, Artieri CG, Wolfner MF, Civetta A, Singh RS (2007) Evolution in the fast lane: rapidly evolving sex-related genes in Drosophila. Genetics 177(3):1321–1335CrossRefPubMedCentralPubMedGoogle Scholar
  15. Hirsh D, Oppenheim D, Klass M (1976) Development of the reproductive system of Caenorhabditis elegans. Dev Biol 49(1):200–219CrossRefPubMedCentralPubMedGoogle Scholar
  16. Igakura T, Kadomatsu K, Kaname T, Muramatsu H, Fan QW, Miyauchi T, Toyama Y, Kuno N, Yuasa S, Takahashi M, Senda T, Taguchi O, Yamamura K, Arimura K, Muramatsu T (1998) A null mutation in basigin, an immunoglobulin superfamily member, indicates its important roles in peri-implantation development and spermatogenesis. Dev Biol 194(2):152–165CrossRefPubMedCentralPubMedGoogle Scholar
  17. Inoue N, Ikawa M, Isotani A, Okabe M (2005) The immunoglobulin superfamily protein Izumo is required for sperm to fuse with eggs. Nature 434(7030):234–238CrossRefPubMedCentralPubMedGoogle Scholar
  18. Inoue N, Nishikawa T, Ikawa M, Okabe M (2012) Tetraspanin-interacting protein IGSF8 is dispensable for mouse fertility. Fertil Steril 98(2):465–470. Scholar
  19. Inoue N, Hamada D, Kamikubo H, Hirata K, Kataoka M, Yamamoto M, Ikawa M, Okabe M, Hagihara Y (2013) Molecular dissection of IZUMO1, a sperm protein essential for sperm-egg fusion. Development 140(15):3221–3229. Scholar
  20. Inoue N, Hagihara Y, Wright D, Suzuki T, Wada I (2015) Oocyte-triggered dimerization of sperm IZUMO1 promotes sperm-egg fusion in mice. Nat Commun 6:8858. Scholar
  21. Jury JA, Frayne J, Hall L (1997) The human fertilin alpha gene is non-functional: implications for its proposed role in fertilization. Biochem J 321(Pt 3):577–581CrossRefPubMedCentralPubMedGoogle Scholar
  22. Karadge UB, Gosto M, Nicotra ML (2015) Allorecognition proteins in an invertebrate exhibit homophilic interactions. Curr Biol 25(21):2845–2850. Scholar
  23. Kato K, Satouh Y, Nishimasu H, Kurabayashi A, Morita J, Fujihara Y, Oji A, Ishitani R, Ikawa M, Nureki O (2016) Structural and functional insights into IZUMO1 recognition by JUNO in mammalian fertilization. Nat Commun 7:12198. Scholar
  24. Kimble J, Ward S (1988) Germ-line development and fertilization. In: Wood WB (ed) The nematode Caenorhabditis elegans. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp 191–213Google Scholar
  25. Krauchunas AR, Singson A (2016) Marriage shrines and worms impacting our understanding of mammalian fertilization. Worm 5(3):e1184389CrossRefPubMedCentralPubMedGoogle Scholar
  26. Krauchunas AR, Marcello MR, Singson A (2016) The molecular complexity of fertilization: introducing the concept of a fertilization synapse. Mol Reprod Dev 83(5):376–386. Scholar
  27. Kroft TL, Gleason EJ, L’Hernault SW (2005) The spe-42 gene is required for sperm-egg interactions during C. elegans fertilization and encodes a sperm-specific transmembrane protein. Dev Biol 286:169–181CrossRefPubMedCentralPubMedGoogle Scholar
  28. L’Hernault SW (1997) Male germline. In: Riddle D, Blumenthal R, Meyer BJ, Priess J (eds) C. elegans II. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp 271–294Google Scholar
  29. L’Hernault SW (2009) The genetics and cell biology of spermatogenesis in the nematode C. elegans. Mol Cell Endocrinol 306(1–2):59–65. Scholar
  30. L’Hernault SW, Singson AW (2000) Developmental genetics of spermatogenesis in the nematode Caenorhabditis elegans. In: Goldberg E (ed) The testes: from stem cell to sperm function, Serono Symposium USA. Springer, New York, pp 109–119Google Scholar
  31. L’Hernault SW, Shakes DC, Ward S (1988) Developmental genetics of chromosome I spermatogenesis-defective mutants in the nematode Caenorhabditis elegans. Genetics 120(2):435–452PubMedPubMedCentralGoogle Scholar
  32. Lorenzetti D, Poirier C, Zhao M, Overbeek PA, Harrison W, Bishop CE (2014) A transgenic insertion on mouse chromosome 17 inactivates a novel immunoglobulin superfamily gene potentially involved in sperm-egg fusion. Mamm Genome 25(3–4):141–148. Scholar
  33. Machaca K, DeFelice LJ, L’Hernault SW (1996) A novel chloride channel localizes to Caenorhabditis elegans spermatids and chloride channel blockers induce spermatid differentiation. Dev Biol 176(1):1–16CrossRefPubMedCentralPubMedGoogle Scholar
  34. McCarter J, Bartlett B, Dang T, Schedl T (1999) On the control of oocyte meiotic maturation and ovulation in Caenorhabditis elegans. Dev Biol 205(1):111–128CrossRefPubMedCentralPubMedGoogle Scholar
  35. Misamore MJ, Gupta S, Snell WJ (2003) The Chlamydomonas Fus1 protein is present on the mating type plus fusion organelle and required for a critical membrane adhesion event during fusion with minus gametes. Mol Biol Cell 14(6):2530–2542CrossRefPubMedCentralPubMedGoogle Scholar
  36. Miyamoto T (2006) The dendritic cell-specific transmembrane protein DC-STAMP is essential for osteoclast fusion and osteoclast bone-resorbing activity. Mod Rheumatol 16(6):341–342CrossRefPubMedCentralPubMedGoogle Scholar
  37. Mori T, Igawa T (2014) Gamete attachment process revealed in flowering plant fertilization. Plant Signal Behav 9(12):e977715. Scholar
  38. Mori T, Igawa T, Tamiya G, Miyagishima SY, Berger F (2014) Gamete attachment requires GEX2 for successful fertilization in Arabidopsis. Curr Biol 24(2):170–175. Scholar
  39. Nelson GA, Ward S (1980) Vesicle fusion, pseudopod extension and amoeboid motility are induced in nematode spermatids by the ionophore monensin. Cell 19(2):457–464CrossRefPubMedCentralPubMedGoogle Scholar
  40. Nishimura H, L’Hernault SW (2010) Spermatogenesis-defective (spe) mutants of the nematode Caenorhabditis elegans provide clues to solve the puzzle of male germline functions during reproduction. Dev Dyn 239(5):1502–1514. Scholar
  41. Nishimura H, L’Hernault SW (2016) Gamete interactions require transmembranous immunoglobulin-like proteins with conserved roles during evolution. Worm 5(3):e1197485CrossRefPubMedCentralPubMedGoogle Scholar
  42. Nishimura H, L’Hernault SW (2017) Spermatogenesis. Curr Biol 27(18):R988–R994. Scholar
  43. Nishimura H, Cho C, Branciforte DR, Myles DG, Primakoff P (2001) Analysis of loss of adhesive function in sperm lacking cyritestin or fertilin beta. Dev Biol 233(1):204–213CrossRefPubMedCentralPubMedGoogle Scholar
  44. Nishimura H, Kim E, Nakanishi T, Baba T (2004) Possible function of the ADAM1a/ADAM2 Fertilin complex in the appearance of ADAM3 on the sperm surface. J Biol Chem 279(33):34957–34962Google Scholar
  45. Nishimura H, Tajima T, Comstra HS, Gleason EJ, L’Hernault SW (2015) The immunoglobulin-like gene spe-45 acts during fertilization in Caenorhabditis elegans like the mouse Izumo1 gene. Curr Biol 25(24):3225–3231. Scholar
  46. Nishimura K, Han L, Bianchi E, Wright GJ, de Sanctis D, Jovine L (2016) The structure of sperm Izumo1 reveals unexpected similarities with Plasmodium invasion proteins. Curr Biol 26(14):R661–R662. Scholar
  47. Ohto U, Ishida H, Krayukhina E, Uchiyama S, Inoue N, Shimizu T (2016) Structure of IZUMO1-JUNO reveals sperm-oocyte recognition during mammalian fertilization. Nature 534(7608):566–569. Scholar
  48. Putiri E, Zannoni S, Kadandale P, Singson A (2004) Functional domains and temperature-sensitive mutations in SPE-9, an EGF repeat-containing protein required for fertility in Caenorhabditis elegans. Dev Biol 272:448–459CrossRefPubMedCentralPubMedGoogle Scholar
  49. Reinke V, Smith HE, Nance J, Wang J, Van Doren C, Begley R, Jones SJ, Davis EB, Scherer S, Ward S, Kim SK (2000) A global profile of germline gene expression in C. elegans. Mol Cell 6(3):605–616CrossRefPubMedCentralPubMedGoogle Scholar
  50. Reinke V, Gil IS, Ward S, Kazmer K (2004) Genome-wide germline-enriched and sex-biased expression profiles in Caenorhabditis elegans. Development 131(2):311–323CrossRefPubMedCentralPubMedGoogle Scholar
  51. Satouh Y, Inoue N, Ikawa M, Okabe M (2012) Visualization of the moment of mouse sperm-egg fusion and dynamic localization of IZUMO1. J Cell Sci 125(Pt 21):4985–4990. Scholar
  52. Saxena DK, Oh-Oka T, Kadomatsu K, Muramatsu T, Toshimori K (2002) Behaviour of a sperm surface transmembrane glycoprotein basigin during epididymal maturation and its role in fertilization in mice. Reproduction 123(3):435–444CrossRefPubMedCentralPubMedGoogle Scholar
  53. Schindl R, Romanin C (2007) Assembly domains in TRP channels. Biochem Soc Trans 35(Pt 1):84–85CrossRefPubMedCentralPubMedGoogle Scholar
  54. Shamsadin R, Adham IM, Nayernia K, Heinlein UA, Oberwinkler H, Engel W (1999) Male mice deficient for germ-cell cyritestin are infertile. Biol Reprod 61(6):1445–1451CrossRefPubMedCentralPubMedGoogle Scholar
  55. Singaravelu G, Chatterjee I, Rahimi S, Druzhinina MK, Kang L, Xu XZ, Singson A (2012) The sperm surface localization of the TRP-3/SPE-41 Ca2+-permeable channel depends on SPE-38 function in Caenorhabditis elegans. Dev Biol 365(2):376–383. Scholar
  56. Singaravelu G, Rahimi S, Krauchunas A, Rizvi A, Dharia S, Shakes D, Smith H, Golden A, Singson A (2015) Forward genetics identifies a requirement for the Izumo-like immunoglobulin superfamily spe-45 gene in Caenorhabditis elegans fertilization. Curr Biol 25(24):3220–3224. Scholar
  57. Singson A, Mercer KB, L’Hernault SW (1998) The C. elegans spe-9 gene encodes a sperm transmembrane protein that contains EGF-like repeats and is required for fertilization. Cell 93:71–79CrossRefPubMedCentralPubMedGoogle Scholar
  58. Swanson WJ, Vacquier VD (2002) The rapid evolution of reproductive proteins. Nat Rev Genet 3(2):137–144CrossRefPubMedCentralPubMedGoogle Scholar
  59. Takayama J, Onami S (2016) The sperm TRP-3 channel mediates the onset of a Ca2+ wave in the fertilized C. elegans oocyte. Cell Rep 15(3):625–637.
  60. Ward S (1986) Asymmetric localization of gene products during the development of Caenorhaditis elegans spermatozoa. In: Gall JG (ed) Gametogenesis and the early embryo. Alan R. Liss, Inc., New York, pp 55–75Google Scholar
  61. Ward S, Carrel JS (1979) Fertilization and sperm competition in the nematode Caenorhabditis elegans. Dev Biol 73(2):304–321CrossRefPubMedCentralPubMedGoogle Scholar
  62. Ward S, Argon Y, Nelson GA (1981) Sperm morphogenesis in wild-type and fertilization-defective mutants of Caenorhabditis elegans. J Cell Biol 91(1):26–44CrossRefPubMedCentralPubMedGoogle Scholar
  63. Wilson KL, Fitch KR, Bafus BT, Wakimoto BT (2006) Sperm plasma membrane breakdown during Drosophila fertilization requires sneaky, an acrosomal membrane protein. Development 133(24):4871–4879CrossRefPubMedCentralPubMedGoogle Scholar
  64. Wilson LD, Obakpolor OA, Jones AM, Richie AL, Mieczkowski BD, Fall GT, Hall RW, Rumbley JN, Kroft TL (2018) The C. elegans spe-49 gene is required for fertilization and encodes a sperm-Specific transmembrane protein homologous to SPE-42. Mol Reprod Dev.
  65. Wolf N, Hirsh D, McIntosh JR (1978) Spermatogenesis in males of the free-living nematode, Caenorhabditis elegans. J Ultrastruct Res 63(2):155–169CrossRefPubMedCentralPubMedGoogle Scholar
  66. Wyckoff GJ, Wang W, Wu CI (2000) Rapid evolution of male reproductive genes in the descent of man. Nature 403(6767):304–309CrossRefPubMedCentralPubMedGoogle Scholar
  67. Xu XZ, Sternberg PM (2003) A C. elegans sperm TRP protein required for sperm-egg interactions during fertilization. Cell 114(3):285–297Google Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Life ScienceSetsunan UniversityOsakaJapan

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