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Intrinsic and extrinsic mechanisms of synapse formation and specificity in C. elegans

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Abstract

Precise neuronal wiring is critical for the function of the nervous system and is ultimately determined at the level of individual synapses. Neurons integrate various intrinsic and extrinsic cues to form synapses onto their correct targets in a stereotyped manner. In the past decades, the nervous system of nematode (Caenorhabditis elegans) has provided the genetic platform to reveal the genetic and molecular mechanisms of synapse formation and specificity. In this review, we will summarize the recent discoveries in synapse formation and specificity in C. elegans.

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References

  1. Watanabe S, Liu Q, Davis MW, Hollopeter G, Thomas N, Jorgensen NB, Jorgensen EM (2013) Ultrafast endocytosis at Caenorhabditis elegans neuromuscular junctions. Elife 2:e00723

    Article  PubMed  PubMed Central  Google Scholar 

  2. White JG, Southgate E, Thomson JN, Brenner S (1986) The structure of the nervous system of the nematode Caenorhabditis elegans. Philos Trans R Soc Lond B Biol Sci 314:1–340

    Article  CAS  PubMed  Google Scholar 

  3. White JG, Southgate E, Thomson JN, Brenner S (1976) The structure of the ventral nerve cord of Caenorhabditis elegans. Philos Trans R Soc Lond B Biol Sci 275:327–348

    Article  CAS  PubMed  Google Scholar 

  4. Nonet ML (1999) Visualization of synaptic specializations in live C. elegans with synaptic vesicle protein-GFP fusions. J Neurosci Methods 89:33–40

    Article  CAS  PubMed  Google Scholar 

  5. Hobert O (2016) Terminal Selectors of Neuronal Identity. Curr Top Dev Biol 116:455–475

    Article  CAS  PubMed  Google Scholar 

  6. Yogev S, Shen K (2014) Cellular and molecular mechanisms of synaptic specificity. Annu Rev Cell Dev Biol 30:417–437

    Article  CAS  PubMed  Google Scholar 

  7. Wen Q, Gao S, Zhen M (2018) Caenorhabditis elegans excitatory ventral cord motor neurons derive rhythm for body undulation. Philos Trans R Soc Lond Ser B, Biol Sci 373:2017037

    Article  CAS  Google Scholar 

  8. Donato A, Kagias K, Zhang Y, Hilliard MA (2019) Neuronal sub-compartmentalization: a strategy to optimize neuronal function. Biol Rev. https://doi.org/10.1111/brv.12487

    Article  PubMed  Google Scholar 

  9. Gan Q, Watanabe S (2018) Synaptic vesicle endocytosis in different model systems. Front Cell Neurosci 12:171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Maeder CI, Shen K, Hoogenraad CC (2014) Axon and dendritic trafficking. Curr Opin Neurobiol 27:165–170

    Article  CAS  PubMed  Google Scholar 

  11. Hirokawa N, Sobue K, Kanda K, Harada A, Yorifuji H (1989) The cytoskeletal architecture of the presynaptic terminal and molecular structure of synapsin 1. J Cell Biol 108:111–126

    Article  CAS  PubMed  Google Scholar 

  12. Xu K, Zhong G, Zhuang X (2013) Actin, spectrin, and associated proteins form a periodic cytoskeletal structure in axons. Science (New York, NY) 339:452–456

    Article  CAS  Google Scholar 

  13. Chia PH, Chen B, Li P, Rosen MK, Shen K (2014) Local F-actin network links synapse formation and axon branching. Cell 156:208–220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chia PH, Patel MR, Shen K (2012) NAB-1 instructs synapse assembly by linking adhesion molecules and F-actin to active zone proteins. Nat Neurosci 15:234–242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mizumoto K, Shen K (2013) Interaxonal interaction defines tiled presynaptic innervation in C. elegans. Neuron 77:655–666

    Article  CAS  PubMed  Google Scholar 

  16. Zhang W, Benson DL (2001) Stages of synapse development defined by dependence on F-actin. J Neurosci 21:5169–5181

    Article  CAS  PubMed  Google Scholar 

  17. Hung W, Hwang C, Po MD, Zhen M (2007) Neuronal polarity is regulated by a direct interaction between a scaffolding protein, Neurabin, and a presynaptic SAD-1 kinase in Caenorhabditis elegans. Development 134:237–249

    Article  CAS  PubMed  Google Scholar 

  18. Hallam SJ, Goncharov A, McEwen J, Baran R, Jin Y (2002) SYD-1, a presynaptic protein with PDZ, C2 and rhoGAP-like domains, specifies axon identity in C. elegans. Nat Neurosci 5:1137–1146

    Article  CAS  PubMed  Google Scholar 

  19. Zhen M, Jin Y (1999) The liprin protein SYD-2 regulates the differentiation of presynaptic termini in C. elegans. Nature 401:371–375

    CAS  PubMed  Google Scholar 

  20. Dai Y, Taru H, Deken SL, Grill B, Ackley B, Nonet ML, Jin Y (2006) SYD-2 liprin-alpha organizes presynaptic active zone formation through ELKS. Nat Neurosci 9:1479–1487

    Article  CAS  PubMed  Google Scholar 

  21. Patel MR, Lehrman EK, Poon VY, Crump JG, Zhen M, Bargmann CI, Shen K (2006) Hierarchical assembly of presynaptic components in defined C. elegans synapses. Nat Neurosci 9:1488–1498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Patel MR, Shen K (2009) RSY-1 is a local inhibitor of presynaptic assembly in C. elegans. Science (New York, NY) 323:1500–1503

    Article  CAS  Google Scholar 

  23. Chia PH, Patel MR, Wagner OI, Klopfenstein DR, Shen K (2013) Intramolecular regulation of presynaptic scaffold protein SYD-2/liprin-alpha. Mol Cell Neurosci 56:76–84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Schoch S, Castillo PE, Jo T, Mukherjee K, Geppert M, Wang Y, Schmitz F, Malenka RC, Sudhof TC (2002) RIM1alpha forms a protein scaffold for regulating neurotransmitter release at the active zone. Nature 415:321–326

    Article  CAS  PubMed  Google Scholar 

  25. Ackley BD, Harrington RJ, Hudson ML, Williams L, Kenyon CJ, Chisholm AD, Jin Y (2005) The two isoforms of the Caenorhabditis elegans leukocyte-common antigen related receptor tyrosine phosphatase PTP-3 function independently in axon guidance and synapse formation. J Neurosci 25:7517–7528

    Article  CAS  PubMed  Google Scholar 

  26. Owald D, Khorramshahi O, Gupta VK, Banovic D, Depner H, Fouquet W, Wichmann C, Mertel S, Eimer S, Reynolds E et al (2012) Cooperation of Syd-1 with Neurexin synchronizes pre- with postsynaptic assembly. Nat Neurosci 15:1219–1226

    Article  CAS  PubMed  Google Scholar 

  27. Stavoe AK, Nelson JC, Martínez-Velázquez LA, Klein M, Samuel AD, Colón-Ramos DA (2012) Synaptic vesicle clustering requires a distinct MIG-10/Lamellipodin isoform and ABI-1 downstream from Netrin. Genes Dev 26:2206–2221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lenfant N, Polanowska J, Bamps S, Omi S, Borg JP, Reboul J (2010) A genome-wide study of PDZ-domain interactions in C. elegans reveals a high frequency of non-canonical binding. BMC Genom 11:671

    Article  CAS  Google Scholar 

  29. Deken SL, Vincent R, Hadwiger G, Liu Q, Wang ZW, Nonet ML (2005) Redundant localization mechanisms of RIM and ELKS in Caenorhabditis elegans. J Neurosci 25:5975–5983

    Article  CAS  PubMed  Google Scholar 

  30. Held RG, Liu C, Kaeser PS (2016) ELKS controls the pool of readily releasable vesicles at excitatory synapses through its N-terminal coiled-coil domains. Elife 5:e14862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dong W, Radulovic T, Goral RO, Thomas C, Suarez Montesinos M, Guerrero-Given D, Hagiwara A, Putzke T, Hida Y, Abe M et al (2018) CAST/ELKS proteins control voltage-gated Ca(2+) channel density and synaptic release probability at a mammalian central synapse. Cell Rep 24:284–293.e286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Crump JG, Zhen M, Jin Y, Bargmann CI (2001) The SAD-1 kinase regulates presynaptic vesicle clustering and axon termination. Neuron 29:115–129

    Article  CAS  PubMed  Google Scholar 

  33. Kim JS, Hung W, Narbonne P, Roy R, Zhen M (2010) C. elegans STRADalpha and SAD cooperatively regulate neuronal polarity and synaptic organization. Development (Cambridge, England) 137:93–102

    Article  CAS  Google Scholar 

  34. Wang Y, Okamoto M, Schmitz F, Hofmann K, Sudhof TC (1997) Rim is a putative Rab3 effector in regulating synaptic-vesicle fusion. Nature 388:593–598

    Article  CAS  PubMed  Google Scholar 

  35. Gracheva EO, Hadwiger G, Nonet ML, Richmond JE (2008) Direct interactions between C. elegans RAB-3 and Rim provide a mechanism to target vesicles to the presynaptic density. Neurosci Lett 444:137–142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. de Jong APH, Roggero CM, Ho MR, Wong MY, Brautigam CA, Rizo J, Kaeser PS (2018) RIM C2B domains target presynaptic active zone functions to PIP2-containing membranes. Neuron 98(335–349):e337

    Google Scholar 

  37. Liu H, Li L, Nedelcu D, Hall Q, Zhou L, Wang W, Yu Y, Kaplan JM, Hu Z (2019) Heterodimerization of UNC-13/RIM regulates synaptic vesicle release probability but not priming in C. elegans. Elife 8:e40585

    Article  PubMed  PubMed Central  Google Scholar 

  38. Xuan Z, Manning L, Nelson J, Richmond JE, Colon-Ramos DA, Shen K, Kurshan PT (2017) Clarinet (CLA-1), a novel active zone protein required for synaptic vesicle clustering and release. Elife 6:e29276

    Article  PubMed  PubMed Central  Google Scholar 

  39. Hallermann S, Kittel RJ, Wichmann C, Weyhersmuller A, Fouquet W, Mertel S, Owald D, Eimer S, Depner H, Schwarzel M et al (2010) Naked dense bodies provoke depression. J Neurosci 30:14340–14345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sutton RB, Fasshauer D, Jahn R, Brunger AT (1998) Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 A resolution. Nature 395:347–353

    Article  CAS  PubMed  Google Scholar 

  41. Gracheva EO, Burdina AO, Holgado AM, Berthelot-Grosjean M, Ackley BD, Hadwiger G, Nonet ML, Weimer RM, Richmond JE (2006) Tomosyn inhibits synaptic vesicle priming in Caenorhabditis elegans. PLoS Biol 4:e261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. McEwen JM, Madison JM, Dybbs M, Kaplan JM (2006) Antagonistic regulation of synaptic vesicle priming by Tomosyn and UNC-13. Neuron 51:303–315

    Article  CAS  PubMed  Google Scholar 

  43. Richmond JE, Davis WS, Jorgensen EM (1999) UNC-13 is required for synaptic vesicle fusion in C. elegans. Nat Neurosci 2:959–964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sassa T, Harada S, Ogawa H, Rand JB, Maruyama IN, Hosono R (1999) Regulation of the UNC-18-Caenorhabditis elegans syntaxin complex by UNC-13. J Neurosci 19:4772–4777

    Article  CAS  PubMed  Google Scholar 

  45. Sitarska E, Xu J, Park S, Liu X, Quade B, Stepien K, Sugita K, Brautigam CA, Sugita S, Rizo J (2017) Autoinhibition of Munc18-1 modulates synaptobrevin binding and helps to enable Munc13-dependent regulation of membrane fusion. Elife 6:e24278

    Article  PubMed  PubMed Central  Google Scholar 

  46. Fujita Y, Shirataki H, Sakisaka T, Asakura T, Ohya T, Kotani H, Yokoyama S, Nishioka H, Matsuura Y, Mizoguchi A et al (1998) Tomosyn: a syntaxin-1-binding protein that forms a novel complex in the neurotransmitter release process. Neuron 20:905–915

    Article  CAS  PubMed  Google Scholar 

  47. Pobbati AV, Razeto A, Boddener M, Becker S, Fasshauer D (2004) Structural basis for the inhibitory role of tomosyn in exocytosis. J Biol Chem 279:47192–47200

    Article  CAS  PubMed  Google Scholar 

  48. Brenner S (1974) The genetics of Caenorhabditis elegans. Genetics 77:71–94

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Gengyo-Ando K, Kamiya Y, Yamakawa A, Kodaira K, Nishiwaki K, Miwa J, Hori I, Hosono R (1993) The C. elegans unc-18 gene encodes a protein expressed in motor neurons. Neuron 11:703–711

    Article  CAS  PubMed  Google Scholar 

  50. Hosono R, Hekimi S, Kamiya Y, Sassa T, Murakami S, Nishiwaki K, Miwa J, Taketo A, Kodaira KI (1992) The unc-18 gene encodes a novel protein affecting the kinetics of acetylcholine metabolism in the nematode Caenorhabditis elegans. J Neurochem 58:1517–1525

    Article  CAS  PubMed  Google Scholar 

  51. Kohn RE, Duerr JS, McManus JR, Duke A, Rakow TL, Maruyama H, Moulder G, Maruyama IN, Barstead RJ, Rand JB (2000) Expression of multiple UNC-13 proteins in the Caenorhabditis elegans nervous system. Mol Biol Cell 11:3441–3452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ahmed S, Maruyama IN, Kozma R, Lee J, Brenner S, Lim L (1992) The Caenorhabditis elegans unc-13 gene product is a phospholipid-dependent high-affinity phorbol ester receptor. Biochem J 287(Pt 3):995–999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Yang X, Wang S, Sheng Y, Zhang M, Zou W, Wu L, Kang L, Rizo J, Zhang R, Xu T et al (2015) Syntaxin opening by the MUN domain underlies the function of Munc13 in synaptic-vesicle priming. Nat Struct Mol Biol 22:547–554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Lu J, Machius M, Dulubova I, Dai H, Sudhof TC, Tomchick DR, Rizo J (2006) Structural basis for a Munc13-1 homodimer to Munc13-1/RIM heterodimer switch. PLoS Biol 4:e192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Camacho M, Basu J, Trimbuch T, Chang S, Pulido-Lozano C, Chang SS, Duluvova I, Abo-Rady M, Rizo J, Rosenmund C (2017) Heterodimerization of Munc13 C2A domain with RIM regulates synaptic vesicle docking and priming. Nat Commun 8:15293

    Article  PubMed  PubMed Central  Google Scholar 

  56. Deng L, Kaeser PS, Xu W, Sudhof TC (2011) RIM proteins activate vesicle priming by reversing autoinhibitory homodimerization of Munc13. Neuron 69:317–331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hata Y, Slaughter CA, Sudhof TC (1993) Synaptic vesicle fusion complex contains unc-18 homologue bound to syntaxin. Nature 366:347–351

    Article  CAS  PubMed  Google Scholar 

  58. Chen X, Lu J, Dulubova I, Rizo J (2008) NMR analysis of the closed conformation of syntaxin-1. J Biomol NMR 41:43–54

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Dulubova I, Sugita S, Hill S, Hosaka M, Fernandez I, Sudhof TC, Rizo J (1999) A conformational switch in syntaxin during exocytosis: role of munc18. EMBO J 18:4372–4382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Park S, Bin NR, Yu B, Wong R, Sitarska E, Sugita K, Ma K, Xu J, Tien CW, Algouneh A et al (2017) UNC-18 and tomosyn antagonistically control synaptic vesicle priming downstream of UNC-13 in Caenorhabditis elegans. J Neurosci 37:8797–8815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Dulubova I, Khvotchev M, Liu S, Huryeva I, Sudhof TC, Rizo J (2007) Munc18-1 binds directly to the neuronal SNARE complex. Proc Natl Acad Sci USA 104:2697–2702

    Article  CAS  PubMed  Google Scholar 

  62. Schaefer AM, Hadwiger GD, Nonet ML (2000) rpm-1, a conserved neuronal gene that regulates targeting and synaptogenesis in C. elegans. Neuron 26:345–356

    Article  CAS  PubMed  Google Scholar 

  63. Wan HI, DiAntonio A, Fetter RD, Bergstrom K, Strauss R, Goodman CS (2000) Highwire regulates synaptic growth in Drosophila. Neuron 26:313–329

    Article  CAS  PubMed  Google Scholar 

  64. Zhen M, Huang X, Bamber B, Jin Y (2000) Regulation of presynaptic terminal organization by C. elegans RPM-1, a putative guanine nucleotide exchanger with a RING-H2 finger domain. Neuron 26:331–343

    Article  CAS  PubMed  Google Scholar 

  65. Bloom AJ, Miller BR, Sanes JR, DiAntonio A (2007) The requirement for Phr1 in CNS axon tract formation reveals the corticostriatal boundary as a choice point for cortical axons. Genes Dev 21:2593–2606

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Collins CA, Wairkar YP, Johnson SL, DiAntonio A (2006) Highwire restrains synaptic growth by attenuating a MAP kinase signal. Neuron 51:57–69

    Article  CAS  PubMed  Google Scholar 

  67. Liao EH, Hung W, Abrams B, Zhen M (2004) An SCF-like ubiquitin ligase complex that controls presynaptic differentiation. Nature 430:345–350

    Article  CAS  PubMed  Google Scholar 

  68. Nakata K, Abrams B, Grill B, Goncharov A, Huang X, Chisholm AD, Jin Y (2005) Regulation of a DLK-1 and p38 MAP kinase pathway by the ubiquitin ligase RPM-1 is required for presynaptic development. Cell 120:407–420

    Article  CAS  PubMed  Google Scholar 

  69. Wu C, Daniels RW, DiAntonio A (2007) DFsn collaborates with Highwire to down-regulate the Wallenda/DLK kinase and restrain synaptic terminal growth. Neural Dev 2:16

    Article  PubMed  PubMed Central  Google Scholar 

  70. Wu C, Wairkar YP, Collins CA, DiAntonio A (2005) Highwire function at the Drosophila neuromuscular junction: spatial, structural, and temporal requirements. J Neurosci 25:9557–9566

    Article  CAS  PubMed  Google Scholar 

  71. Grill B, Chen L, Tulgren ED, Baker ST, Bienvenut W, Anderson M, Quadroni M, Jin Y, Garner CC (2012) RAE-1, a novel PHR binding protein, is required for axon termination and synapse formation in Caenorhabditis elegans. J Neurosci 32:2628–2636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Hammarlund M, Nix P, Hauth L, Jorgensen EM, Bastiani M (2009) Axon regeneration requires a conserved MAP kinase pathway. Science (New York, NY) 323:802–806

    Article  CAS  Google Scholar 

  73. Stavoe AK, Hill SE, Hall DH, Colon-Ramos DA (2016) KIF1A/UNC-104 transports ATG-9 to regulate neurodevelopment and autophagy at synapses. Dev Cell 38:171–185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hall DH, Hedgecock EM (1991) Kinesin-related gene unc-104 is required for axonal transport of synaptic vesicles in C. elegans. Cell 65:837–847

    Article  CAS  PubMed  Google Scholar 

  75. Klassen MP, Wu YE, Maeder CI, Nakae I, Cueva JG, Lehrman EK, Tada M, Gengyo-Ando K, Wang GJ, Goodman M et al (2010) An Arf-like small G protein, ARL-8, promotes the axonal transport of presynaptic cargoes by suppressing vesicle aggregation. Neuron 66:710–723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Lipton DM, Maeder CI, Shen K (2018) Rapid assembly of presynaptic materials behind the growth cone in dopaminergic neurons is mediated by precise regulation of axonal transport. Cell Rep 24:2709–2722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Niwa S, Lipton DM, Morikawa M, Zhao C, Hirokawa N, Lu H, Shen K (2016) Autoinhibition of a neuronal kinesin UNC-104/KIF1A regulates the size and density of synapses. Cell Rep 16:2129–2141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Wu YE, Huo L, Maeder CI, Feng W, Shen K (2013) The balance between capture and dissociation of presynaptic proteins controls the spatial distribution of synapses. Neuron 78:994–1011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Niwa S, Tao L, Lu SY, Liew GM, Feng W, Nachury MV, Shen K (2017) BORC regulates the axonal transport of synaptic vesicle precursors by activating ARL-8. Curr Biol 27(2569–2578):e2564

    Google Scholar 

  80. Shin H, Wyszynski M, Huh KH, Valtschanoff JG, Lee JR, Ko J, Streuli M, Weinberg RJ, Sheng M, Kim E (2003) Association of the kinesin motor KIF1A with the multimodular protein liprin-alpha. J Biol Chem 278:11393–11401

    Article  CAS  PubMed  Google Scholar 

  81. Wagner OI, Esposito A, Kohler B, Chen CW, Shen CP, Wu GH, Butkevich E, Mandalapu S, Wenzel D, Wouters FS et al (2009) Synaptic scaffolding protein SYD-2 clusters and activates kinesin-3 UNC-104 in C. elegans. Proc Natl Acad Sci USA 106:19605–19610

    Article  PubMed  Google Scholar 

  82. Hall DH, Russell RL (1991) The posterior nervous system of the nematode Caenorhabditis elegans: serial reconstruction of identified neurons and complete pattern of synaptic interactions. J Neurosci 11:1–22

    Article  CAS  PubMed  Google Scholar 

  83. Sawa H, Korswagen HC (2013) Wnt signaling in C. elegans. WormBook: the online review of C. elegans biology. 1–30. https://doi.org/10.1895/wormbook.1.7.2

  84. Klassen MP, Shen K (2007) Wnt signaling positions neuromuscular connectivity by inhibiting synapse formation in C. elegans. Cell 130:704–716

    Article  CAS  PubMed  Google Scholar 

  85. Mizumoto K, Shen K (2013) Two Wnts instruct topographic synaptic innervation in C. elegans. Cell Rep 5:389–396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Kurshan PT, Merrill SA, Dong Y, Ding C, Hammarlund M, Bai J, Jorgensen EM, Shen K (2018) gamma-neurexin and frizzled mediate parallel synapse assembly pathways antagonized by receptor endocytosis. Neuron 100:150–166.e154

    Article  CAS  PubMed  Google Scholar 

  87. Davis EK, Zou Y, Ghosh A (2008) Wnts acting through canonical and noncanonical signaling pathways exert opposite effects on hippocampal synapse formation. Neural Dev 3:32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Inaki M, Yoshikawa S, Thomas JB, Aburatani H, Nose A (2007) Wnt4 is a local repulsive cue that determines synaptic target specificity. Curr Biol 17:1574–1579

    Article  CAS  PubMed  Google Scholar 

  89. Packard M, Koo ES, Gorczyca M, Sharpe J, Cumberledge S, Budnik V (2002) The Drosophila Wnt, wingless, provides an essential signal for pre- and postsynaptic differentiation. Cell 111:319–330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Cerpa W, Gambrill A, Inestrosa NC, Barria A (2011) Regulation of NMDA-receptor synaptic transmission by Wnt signaling. J Neurosci 31:9466–9471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Sahores M, Gibb A, Salinas PC (2010) Frizzled-5, a receptor for the synaptic organizer Wnt7a, regulates activity-mediated synaptogenesis. Development (Cambridge, England) 137:2215–2225

    Article  CAS  Google Scholar 

  92. Hedgecock EM, Culotti JG, Hall DH (1990) The unc-5, unc-6, and unc-40 genes guide circumferential migrations of pioneer axons and mesodermal cells on the epidermis in C. elegans. Neuron 4:61–85

    Article  CAS  PubMed  Google Scholar 

  93. Ishii N, Wadsworth WG, Stern BD, Culotti JG, Hedgecock EM (1992) UNC-6, a laminin-related protein, guides cell and pioneer axon migrations in C. elegans. Neuron 9:873–881

    Article  CAS  PubMed  Google Scholar 

  94. Kennedy TE, Serafini T, de la Torre JR, Tessier-Lavigne M (1994) Netrins are diffusible chemotropic factors for commissural axons in the embryonic spinal cord. Cell 78:425–435

    Article  CAS  PubMed  Google Scholar 

  95. Serafini T, Kennedy TE, Galko MJ, Mirzayan C, Jessell TM, Tessier-Lavigne M (1994) The netrins define a family of axon outgrowth-promoting proteins homologous to C. elegans UNC-6. Cell 78:409–424

    Article  CAS  PubMed  Google Scholar 

  96. Wadsworth WG, Bhatt H, Hedgecock EM (1996) Neuroglia and pioneer neurons express UNC-6 to provide global and local netrin cues for guiding migrations in C. elegans. Neuron 16:35–46

    Article  CAS  PubMed  Google Scholar 

  97. Su M, Merz DC, Killeen MT, Zhou Y, Zheng H, Kramer JM, Hedgecock EM, Culotti JG (2000) Regulation of the UNC-5 netrin receptor initiates the first reorientation of migrating distal tip cells in Caenorhabditis elegans. Development (Cambridge, England) 127:585–594

    CAS  Google Scholar 

  98. Hong K, Hinck L, Nishiyama M, Poo MM, Tessier-Lavigne M, Stein E (1999) A ligand-gated association between cytoplasmic domains of UNC5 and DCC family receptors converts netrin-induced growth cone attraction to repulsion. Cell 97:927–941

    Article  CAS  PubMed  Google Scholar 

  99. Leung-Hagesteijn C, Spence AM, Stern BD, Zhou Y, Su MW, Hedgecock EM, Culotti JG (1992) UNC-5, a transmembrane protein with immunoglobulin and thrombospondin type 1 domains, guides cell and pioneer axon migrations in C. elegans. Cell 71:289–299

    Article  CAS  PubMed  Google Scholar 

  100. Chan SS, Zheng H, Su MW, Wilk R, Killeen MT, Hedgecock EM, Culotti JG (1996) UNC-40, a C. elegans homolog of DCC (deleted in colorectal cancer), is required in motile cells responding to UNC-6 netrin cues. Cell 87:187–195

    Article  CAS  PubMed  Google Scholar 

  101. Keino-Masu K, Masu M, Hinck L, Leonardo ED, Chan SS, Culotti JG, Tessier-Lavigne M (1996) Deleted in colorectal cancer (DCC) encodes a netrin receptor. Cell 87:175–185

    Article  CAS  PubMed  Google Scholar 

  102. Kolodziej PA, Timpe LC, Mitchell KJ, Fried SR, Goodman CS, Jan LY, Jan YN (1996) Frazzled encodes a Drosophila member of the DCC immunoglobulin subfamily and is required for CNS and motor axon guidance. Cell 87:197–204

    Article  CAS  PubMed  Google Scholar 

  103. Poon VY, Klassen MP, Shen K (2008) UNC-6/netrin and its receptor UNC-5 locally exclude presynaptic components from dendrites. Nature 455:669–673

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Ou CY, Poon VY, Maeder CI, Watanabe S, Lehrman EK, Fu AK, Park M, Fu WY, Jorgensen EM, Ip NY et al (2010) Two cyclin-dependent kinase pathways are essential for polarized trafficking of presynaptic components. Cell 141:846–858

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Colon-Ramos DA, Margeta MA, Shen K (2007) Glia promote local synaptogenesis through UNC-6 (netrin) signaling in C elegans. Science (New York, NY) 318:103–106

    Article  CAS  Google Scholar 

  106. Shao Z, Watanabe S, Christensen R, Jorgensen EM, Colon-Ramos DA (2013) Synapse location during growth depends on glia location. Cell 154:337–350

    Article  CAS  PubMed  Google Scholar 

  107. Goldman JS, Ashour MA, Magdesian MH, Tritsch NX, Harris SN, Christofi N, Chemali R, Stern YE, Thompson-Steckel G, Gris P et al (2013) Netrin-1 promotes excitatory synaptogenesis between cortical neurons by initiating synapse assembly. J Neurosci 33:17278–17289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Stavoe AK, Colón-Ramos DA (2012) Netrin instructs synaptic vesicle clustering through Rac GTPase, MIG-10, and the actin cytoskeleton. J Cell Biol 197:75–88

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Park J, Knezevich PL, Wung W, O’Hanlon SN, Goyal A, Benedetti KL, Barsi-Rhyne BJ, Raman M, Mock N, Bremer M et al (2011) A conserved juxtacrine signal regulates synaptic partner recognition in Caenorhabditis elegans. Neural Dev 6:28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Varshney A, Benedetti K, Watters K, Shankar R, Tatarakis D, Coto Villa D, Magallanes K, Agenor V, Wung W, Farah F et al (2018) The receptor protein tyrosine phosphatase CLR-1 is required for synaptic partner recognition. PLoS Genet 14:e1007312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Teichmann HM, Shen K (2011) UNC-6 and UNC-40 promote dendritic growth through PAR-4 in Caenorhabditis elegans neurons. Nat Neurosci 14:165–172

    Article  CAS  PubMed  Google Scholar 

  112. Tran TS, Kolodkin AL, Bharadwaj R (2007) Semaphorin regulation of cellular morphology. Annu Rev Cell Dev Biol 23:263–292

    Article  CAS  PubMed  Google Scholar 

  113. Joo WJ, Sweeney LB, Liang L, Luo L (2013) Linking cell fate, trajectory choice, and target selection: genetic analysis of Sema-2b in olfactory axon targeting. Neuron 78:673–686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Tran TS, Rubio ME, Clem RL, Johnson D, Case L, Tessier-Lavigne M, Huganir RL, Ginty DD, Kolodkin AL (2009) Secreted semaphorins control spine distribution and morphogenesis in the postnatal CNS. Nature 462:1065–1069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Chen X, Shibata AC, Hendi A, Kurashina M, Fortes E, Weilinger NL, MacVicar BA, Murakoshi H, Mizumoto K (2018) Rap2 and TNIK control Plexin-dependent tiled synaptic innervation in C elegans. eLife 7:e38801

    Article  PubMed  PubMed Central  Google Scholar 

  116. Matigian N, Windus L, Smith H, Filippich C, Pantelis C, McGrath J, Mowry B, Hayward N (2007) Expression profiling in monozygotic twins discordant for bipolar disorder reveals dysregulation of the WNT signalling pathway. Mol Psychiatry 12:815–825

    Article  CAS  PubMed  Google Scholar 

  117. Anazi S, Shamseldin HE, AlNaqeb D, Abouelhoda M, Monies D, Salih MA, Al-Rubeaan K, Alkuraya FS (2016) A null mutation in TNIK defines a novel locus for intellectual disability. Hum Genet 135:773–778

    Article  CAS  PubMed  Google Scholar 

  118. Shi J, Levinson DF, Duan J, Sanders AR, Zheng Y, Pe’er I, Dudbridge F, Holmans PA, Whittemore AS, Mowry BJ et al (2009) Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 460:753–757

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Shen K, Bargmann CI (2003) The immunoglobulin superfamily protein SYG-1 determines the location of specific synapses in C. elegans. Cell 112:619–630

    Article  CAS  PubMed  Google Scholar 

  120. Shen K, Fetter RD, Bargmann CI (2004) Synaptic specificity is generated by the synaptic guidepost protein SYG-2 and its receptor, SYG-1. Cell 116:869–881

    Article  CAS  PubMed  Google Scholar 

  121. Bhalla K, Luo Y, Buchan T, Beachem MA, Guzauskas GF, Ladd S, Bratcher SJ, Schroer RJ, Balsamo J, DuPont BR et al (2008) Alterations in CDH15 and KIRREL3 in patients with mild to severe intellectual disability. Am J Hum Genet 83:703–713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Ozkan E, Chia PH, Wang RR, Goriatcheva N, Borek D, Otwinowski Z, Walz T, Shen K, Garcia KC (2014) Extracellular architecture of the SYG-1/SYG-2 adhesion complex instructs synaptogenesis. Cell 156:482–494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Ding M, Chao D, Wang G, Shen K (2007) Spatial regulation of an E3 ubiquitin ligase directs selective synapse elimination. Science (New York, NY) 317:947–951

    Article  CAS  Google Scholar 

  124. Chao DL, Shen K (2008) Functional dissection of SYG-1 and SYG-2, cell adhesion molecules required for selective synaptogenesis in C. elegans. Mol Cell Neurosci 39:248–257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Cherra SJ 3rd, Jin Y (2016) A two-immunoglobulin-domain transmembrane protein mediates an epidermal-neuronal interaction to maintain synapse density. Neuron 89:325–336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Howell K, White JG, Hobert O (2015) Spatiotemporal control of a novel synaptic organizer molecule. Nature 523:83–87

    Article  CAS  PubMed  Google Scholar 

  127. Francis MM, Evans SP, Jensen M, Madsen DM, Mancuso J, Norman KR, Maricq AV (2005) The Ror receptor tyrosine kinase CAM-1 is required for ACR-16-mediated synaptic transmission at the C. elegans neuromuscular junction. Neuron 46:581–594

    Article  CAS  PubMed  Google Scholar 

  128. Jensen M, Hoerndli FJ, Brockie PJ, Wang R, Johnson E, Maxfield D, Francis MM, Madsen DM, Maricq AV (2012) Wnt signaling regulates acetylcholine receptor translocation and synaptic plasticity in the adult nervous system. Cell 149:173–187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Hoerndli FJ, Wang R, Mellem JE, Kallarackal A, Brockie PJ, Thacker C, Madsen DM, Maricq AV (2015) Neuronal activity and CaMKII regulate kinesin-mediated transport of synaptic AMPARs. Neuron 86:457–474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Rongo C, Kaplan JM (1999) CaMKII regulates the density of central glutamatergic synapses in vivo. Nature 402:195–199

    Article  CAS  PubMed  Google Scholar 

  131. Juo P, Harbaugh T, Garriga G, Kaplan JM (2007) CDK-5 regulates the abundance of GLR-1 glutamate receptors in the ventral cord of Caenorhabditis elegans. Mol Biol Cell 18:3883–3893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Monteiro MI, Ahlawat S, Kowalski JR, Malkin E, Koushika SP, Juo P (2012) The kinesin-3 family motor KLP-4 regulates anterograde trafficking of GLR-1 glutamate receptors in the ventral nerve cord of Caenorhabditis elegans. Mol Biol Cell 23:3647–3662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Hoerndli FJ, Maxfield DA, Brockie PJ, Mellem JE, Jensen E, Wang R, Madsen DM, Maricq AV (2013) Kinesin-1 regulates synaptic strength by mediating the delivery, removal, and redistribution of AMPA receptors. Neuron 80:1421–1437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Seetharaman A, Selman G, Puckrin R, Barbier L, Wong E, D’Souza SA, Roy PJ (2011) MADD-4 is a secreted cue required for midline-oriented guidance in Caenorhabditis elegans. Dev Cell 21:669–680

    Article  CAS  PubMed  Google Scholar 

  135. Pinan-Lucarre B, Tu H, Pierron M, Cruceyra PI, Zhan H, Stigloher C, Richmond JE, Bessereau JL (2014) C. elegans Punctin specifies cholinergic versus GABAergic identity of postsynaptic domains. Nature 511:466–470

    Article  CAS  PubMed  Google Scholar 

  136. Chen LY, Jiang M, Zhang B, Gokce O, Sudhof TC (2017) Conditional deletion of all neurexins defines diversity of essential synaptic organizer functions for neurexins. Neuron 94:611–625.e614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Graf ER, Zhang X, Jin SX, Linhoff MW, Craig AM (2004) Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins. Cell 119:1013–1026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Dean C, Scholl FG, Choih J, DeMaria S, Berger J, Isacoff E, Scheiffele P (2003) Neurexin mediates the assembly of presynaptic terminals. Nat Neurosci 6:708–716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Scheiffele P, Fan J, Choih J, Fetter R, Serafini T (2000) Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons. Cell 101:657–669

    Article  CAS  PubMed  Google Scholar 

  140. Maro GS, Gao S, Olechwier AM, Hung WL, Liu M, Ozkan E, Zhen M, Shen K (2015) MADD-4/punctin and neurexin organize C. elegans GABAergic postsynapses through neuroligin. Neuron 86:1420–1432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Tu H, Pinan-Lucarre B, Ji T, Jospin M, Bessereau JL (2015) C. elegans punctin clusters GABA(A) receptors via neuroligin binding and UNC-40/DCC recruitment. Neuron 86:1407–1419

    Article  CAS  PubMed  Google Scholar 

  142. Philbrook A, Ramachandran S, Lambert CM, Oliver D, Florman J, Alkema MJ, Lemons M, Francis MM (2018) Neurexin directs partner-specific synaptic connectivity in C. elegans. Elife 7:e35692

    Article  PubMed  PubMed Central  Google Scholar 

  143. Gally C, Eimer S, Richmond JE, Bessereau JL (2004) A transmembrane protein required for acetylcholine receptor clustering in Caenorhabditis elegans. Nature 431:578–582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Gendrel M, Rapti G, Richmond JE, Bessereau JL (2009) A secreted complement-control-related protein ensures acetylcholine receptor clustering. Nature 461:992–996

    Article  CAS  PubMed  Google Scholar 

  145. Rapti G, Richmond J, Bessereau JL (2011) A single immunoglobulin-domain protein required for clustering acetylcholine receptors in C. elegans. EMBO J 30:706–718

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Jarrell TA, Wang Y, Bloniarz AE, Brittin CA, Xu M, Thomson JN, Albertson DG, Hall DH, Emmons SW (2012) The connectome of a decision-making neural network. Science (New York, NY) 337:437–444

    Article  CAS  Google Scholar 

  147. Oren-Suissa M, Bayer EA, Hobert O (2016) Sex-specific pruning of neuronal synapses in Caenorhabditis elegans. Nature 533:206–211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Feinberg EH, Vanhoven MK, Bendesky A, Wang G, Fetter RD, Shen K, Bargmann CI (2008) GFP reconstitution across synaptic partners (GRASP) defines cell contacts and synapses in living nervous systems. Neuron 57:353–363

    Article  CAS  PubMed  Google Scholar 

  149. Hilliard MA, Bargmann CI, Bazzicalupo P (2002) C. elegans responds to chemical repellents by integrating sensory inputs from the head and the tail. Curr Biol 12:730–734

    Article  CAS  PubMed  Google Scholar 

  150. Weinberg P, Berkseth M, Zarkower D, Hobert O (2018) Sexually dimorphic unc-6/Netrin expression controls sex-specific maintenance of synaptic connectivity. Curr Biol 28(623–629):e623

    Article  CAS  Google Scholar 

  151. Bayer EA, Hobert O (2018) Past experience shapes sexually dimorphic neuronal wiring through monoaminergic signalling. Nature 561:117–121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Thompson-Peer KL, Bai J, Hu Z, Kaplan JM (2012) HBL-1 patterns synaptic remodeling in C. elegans. Neuron 73:453–465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Hart MP, Hobert O (2018) Neurexin controls plasticity of a mature, sexually dimorphic neuron. Nature 553:165–170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Schiavo G, Benfenati F, Poulain B, Rossetto O, Polverino de Laureto P, DasGupta BR, Montecucco C (1992) Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin. Nature 359:832–835

    Article  CAS  PubMed  Google Scholar 

  155. Lopez-Cruz A, Sordillo A, Pokala N, Liu Q, McGrath PT, Bargmann CI (2019) Parallel multimodal circuits control an innate foraging behavior. Neuron 102(2):407–419

    Article  CAS  PubMed  Google Scholar 

  156. Jang H, Kim K, Neal SJ, Macosko E, Kim D, Butcher RA, Zeiger DM, Bargmann CI, Sengupta P (2012) Neuromodulatory state and sex specify alternative behaviors through antagonistic synaptic pathways in C. elegans. Neuron 75:585–592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Gordus A, Pokala N, Levy S, Flavell SW, Bargmann CI (2015) Feedback from network states generates variability in a probabilistic olfactory circuit. Cell 161:215–227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Barbagallo B, Philbrook A, Touroutine D, Banerjee N, Oliver D, Lambert CM, Francis MM (2017) Excitatory neurons sculpt GABAergic neuronal connectivity in the C. elegans motor circuit. Development (Cambridge, England) 144:1807–1819

    Article  CAS  Google Scholar 

  159. Lin JY, Sann SB, Zhou K, Nabavi S, Proulx CD, Malinow R, Jin Y, Tsien RY (2013) Optogenetic inhibition of synaptic release with chromophore-assisted light inactivation (CALI). Neuron 79:241–253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Pokala N, Liu Q, Gordus A, Bargmann CI (2014) Inducible and titratable silencing of Caenorhabditis elegans neurons in vivo with histamine-gated chloride channels. Proc Natl Acad Sci USA 111:2770–2775

    Article  CAS  PubMed  Google Scholar 

  161. Nagel G, Szellas T, Huhn W, Kateriya S, Adeishvili N, Berthold P, Ollig D, Hegemann P, Bamberg E (2003) Channelrhodopsin-2, a directly light-gated cation-selective membrane channel. Proc Natl Acad Sci USA 100:13940–13945

    Article  CAS  PubMed  Google Scholar 

  162. Zhang L, Ward JD, Cheng Z, Dernburg AF (2015) The auxin-inducible degradation (AID) system enables versatile conditional protein depletion in C. elegans. Development (Cambridge, England) 142:4374–4384

    Article  CAS  Google Scholar 

  163. Armenti ST, Lohmer LL, Sherwood DR, Nance J (2014) Repurposing an endogenous degradation system for rapid and targeted depletion of C. elegans proteins. Development (Cambridge, England) 141:4640–4647

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful to Harald Hutter and Shinsuke Niwa for comments on the manuscript. We also thank members of the Mizumoto lab for general discussions. This work is supported by HFSP (CDA-00004/2014), CIHR (PJT-148667) and NSERC (RGPIN-2015-04022). KM is a recipient of Canada Research Chair and Michael Smith Foundation for Health Research Scholar.

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    1. Department of Zoology, The University of British Columbia, 2406-2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada

      Ardalan Hendi, Mizuki Kurashina & Kota Mizumoto

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    1. Ardalan Hendi
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    Hendi, A., Kurashina, M. & Mizumoto, K. Intrinsic and extrinsic mechanisms of synapse formation and specificity in C. elegans. Cell. Mol. Life Sci. 76, 2719–2738 (2019). https://doi.org/10.1007/s00018-019-03109-1

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