Abstract
Among all the biological systems in vertebrates, the central nervous system (CNS) is the most complex, and its function depends on specialized contacts among neurons called synapses. The assembly and organization of synapses must be exquisitely regulated for a normal brain function and network activity. There has been a tremendous effort in recent decades to understand the molecular and cellular mechanisms participating in the formation of new synapses and their organization, maintenance, and regulation. At the vertebrate presynapses, proteins such as Piccolo, Bassoon, RIM, RIM-BPs, CAST/ELKS, liprin-α, and Munc13 are constant residents and participate in multiple and dynamic interactions with other regulatory proteins, which define network activity and normal brain function. Here, we review the function of these active zone (AZ) proteins and diverse factors involved in AZ assembly and maintenance, with an emphasis on axonal trafficking of precursor vesicles, protein homo- and hetero-oligomeric interactions as a mechanism of AZ trapping and stabilization, and the role of F-actin in presynaptic assembly and its modulation by Wnt signaling.
Similar content being viewed by others
References
Alabi AA, Tsien RW (2012) Synaptic vesicle pools and dynamics. Cold Spring Harb Perspect Biol 4:a013680. doi:10.1101/cshperspect.a013680
Garner CC, Kindler S, Gundelfinger ED (2000) Molecular determinants of presynaptic active zones. Curr Opin Neurobiol 10:321–327
Schoch S, Gundelfinger ED (2006) Molecular organization of the presynaptic active zone. Cell Tissue Res 326:379–391. doi:10.1007/s00441-006-0244-y
Torres VI, Vallejo D, Inestrosa NC (2017) Emerging synaptic molecules as candidates in the etiology of neurological disorders. Neural Plast 2017:1–25. doi:10.1155/2017/8081758
Ahmari SE, Buchanan J, Smith SJ (2000) Assembly of presynaptic active zones from cytoplasmic transport packets. Nat Neurosci 3:445–451. doi:10.1038/74814
Maas C, Torres VI, Altrock WD et al (2012) Formation of Golgi-derived active zone precursor vesicles. J Neurosci 32:11095–11108. doi:10.1523/JNEUROSCI.0195-12.2012
Tao-Cheng J-H (2007) Ultrastructural localization of active zone and synaptic vesicle proteins in a preassembled multi-vesicle transport aggregate. Neuroscience 150:575–584. doi:10.1016/j.neuroscience.2007.09.031
Zhai RG, Vardinon-Friedman H, Cases-Langhoff C et al (2001) Assembling the presynaptic active zone: a characterization of an active one precursor vesicle. Neuron 29:131–143
van den Berg R, Hoogenraad CC (2012) Molecular motors in cargo trafficking and synapse assembly. Advances in experimental medicine and biology, In, pp. 173–196
Fejtova A, Davydova D, Bischof F et al (2009) Dynein light chain regulates axonal trafficking and synaptic levels of bassoon. J Cell Biol 185:341–355. doi:10.1083/jcb.200807155
Cases-Langhoff C, Voss B, Garner AM et al (1996) Piccolo, a novel 420 kDa protein associated with the presynaptic cytomatrix. Eur J Cell Biol 69:214–223
Fenster SD, Chung WJ, Zhai R et al (2000) Piccolo, a presynaptic zinc finger protein structurally related to bassoon. Neuron 25:203–214
Gundelfinger ED, Reissner C, Garner CC (2016) Role of bassoon and piccolo in assembly and molecular organization of the active zone. Front Synaptic Neurosci 7:19. doi:10.3389/fnsyn.2015.00019
Kim S, Ko J, Shin H et al (2003) The GIT family of proteins forms multimers and associates with the presynaptic cytomatrix protein piccolo. J Biol Chem 278:6291–6300. doi:10.1074/jbc.M212287200
Fenster SD, Kessels MM, Qualmann B et al (2003) Interactions between piccolo and the actin/dynamin-binding protein Abp1 link vesicle endocytosis to presynaptic active zones. J Biol Chem 278:20268–20277. doi:10.1074/jbc.M210792200
Gerber SH, Garcia J, Rizo J, Südhof TC (2001) An unusual C(2)-domain in the active-zone protein piccolo: implications for Ca(2+) regulation of neurotransmitter release. EMBO J 20:1605–1619. doi:10.1093/emboj/20.7.1605
Müller CS, Haupt A, Bildl W et al (2010) Quantitative proteomics of the Cav2 channel nano-environments in the mammalian brain. Proc Natl Acad Sci U S A 107:14950–14957. doi:10.1073/pnas.1005940107
Wagh D, Terry-Lorenzo R, Waites CL et al (2015) Piccolo directs activity dependent F-actin assembly from presynaptic active zones via Daam1. PLoS One 10:e0120093. doi:10.1371/journal.pone.0120093
Terry-Lorenzo RT, Torres VI, Wagh D et al (2016) Trio, a rho family GEF, interacts with the presynaptic active zone proteins piccolo and bassoon. PLoS One 11:e0167535. doi:10.1371/journal.pone.0167535
Leal-Ortiz S, Waites CL, Terry-Lorenzo R et al (2008) Piccolo modulation of synapsin1a dynamics regulates synaptic vesicle exocytosis. J Cell Biol 181:831–846. doi:10.1083/jcb.200711167
Waites CL, Leal-Ortiz SA, Andlauer TFM et al (2011) Piccolo regulates the dynamic assembly of presynaptic F-actin. J Neurosci Off J Soc Neurosci 31:14250–14263. doi:10.1523/JNEUROSCI.1835-11.2011
Regus-Leidig H, Ott C, Löhner M et al (2013) Identification and immunocytochemical characterization of piccolino, a novel piccolo splice variant selectively expressed at sensory ribbon synapses of the eye and ear. PLoS One 8:e70373. doi:10.1371/journal.pone.0070373
Regus-Leidig H, Fuchs M, Löhner M et al (2014) In vivo knockdown of piccolino disrupts presynaptic ribbon morphology in mouse photoreceptor synapses. Front Cell Neurosci 8:259. doi:10.3389/fncel.2014.00259
Cochilla AJ, Angleson JK, Betz WJ (1999) Monitoring secretory membrane with fm1-43 fluorescence. Annu Rev Neurosci 22:1–10. doi:10.1146/annurev.neuro.22.1.1
Mukherjee K, Yang X, Gerber SH et al (2010) Piccolo and bassoon maintain synaptic vesicle clustering without directly participating in vesicle exocytosis. Proc Natl Acad Sci 107:6504–6509. doi:10.1073/pnas.1002307107
Bruckner JJ, Gratz SJ, Slind JK et al (2012) Fife, a Drosophila Piccolo-RIM homolog, promotes active zone organization and neurotransmitter release. J Neurosci 32:17048–17058. doi:10.1523/JNEUROSCI.3267-12.2012
Bruckner JJ, Zhan H, Gratz SJ et al (2017) Fife organizes synaptic vesicles and calcium channels for high-probability neurotransmitter release. J Cell Biol 216:231–246. doi:10.1083/jcb.201601098
Dieck S, Sanmartí-Vila L, Langnaese K et al (1998) Bassoon, a novel zinc-finger CAG/glutamine-repeat protein selectively localized at the active zone of presynaptic nerve terminals. J Cell Biol 142:499–509
Wang X, Kibschull M, Laue MM et al (1999) Aczonin, a 550-kD putative scaffolding protein of presynaptic active zones, shares homology regions with rim and bassoon and binds profilin. J Cell Biol 147:151–162
Dieck S, Altrock WD, Kessels MM et al (2005) Molecular dissection of the photoreceptor ribbon synapse. J Cell Biol 168:825–836. doi:10.1083/jcb.200408157
Khimich D, Nouvian R, Pujol R et al (2005) Hair cell synaptic ribbons are essential for synchronous auditory signalling. Nature 434:889–894. doi:10.1038/nature03418
Regus-Leidig H, Dieck S, Brandstätter JH (2010) Absence of functional active zone protein bassoon affects assembly and transport of ribbon precursors during early steps of photoreceptor synaptogenesis. Eur J Cell Biol 89:468–475. doi:10.1016/j.ejcb.2009.12.006
Altrock WD, Dieck S, Sokolov M et al (2003) Functional inactivation of a fraction of excitatory synapses in mice deficient for the active zone protein bassoon. Neuron 37:787–800
Hallermann S, Fejtova A, Schmidt H et al (2010) Bassoon speeds vesicle reloading at a central excitatory synapse. Neuron 68:710–723. doi:10.1016/j.neuron.2010.10.026
Davydova D, Marini C, King C et al (2014) Bassoon specifically controls presynaptic P/Q-type Ca2+ channels via RIM-binding protein. Neuron 82:181–194. doi:10.1016/j.neuron.2014.02.012
Dick O, Dieck S, Altrock WD et al (2003) The presynaptic active zone protein bassoon is essential for photoreceptor ribbon synapse formation in the retina. Neuron 37:775–786
Frank T, Rutherford MA, Strenzke N et al (2010) Bassoon and the synaptic ribbon organize Ca2+ channels and vesicles to add release sites and promote refilling. Neuron 68:724–738. doi:10.1016/j.neuron.2010.10.027
Jing Z, Rutherford MA, Takago H et al (2013) Disruption of the presynaptic cytomatrix protein bassoon degrades ribbon anchorage, multiquantal release, and sound encoding at the hair cell afferent synapse. J Neurosci Off J Soc Neurosci 33:4456–4467. doi:10.1523/JNEUROSCI.3491-12.2013
Mendoza Schulz A, Jing Z, Sánchez Caro JM et al (2014) Bassoon-disruption slows vesicle replenishment and induces homeostatic plasticity at a CNS synapse. EMBO J 33:512–527. doi:10.1002/embj.201385887
Ahmed S, Wittenmayer N, Kremer T et al (2013) Mover is a homomeric phospho-protein present on synaptic vesicles. PLoS One 8:e63474. doi:10.1371/journal.pone.0063474
Körber C, Horstmann H, Venkataramani V et al (2015) Modulation of presynaptic release probability by the vertebrate-specific protein mover. Neuron 87:521–533. doi:10.1016/j.neuron.2015.07.001
Waites CL, Leal-Ortiz SA, Okerlund N et al (2013) Bassoon and piccolo maintain synapse integrity by regulating protein ubiquitination and degradation. EMBO J 32:954–969. doi:10.1038/emboj.2013.27
Ivanova D, Dirks A, Montenegro-Venegas C et al (2015) Synaptic activity controls localization and function of CtBP1 via binding to bassoon and piccolo. The EMBO journal 34:1056–1077. doi:10.15252/embj.201488796
Okerlund ND, Schneider K, Leal-Ortiz S et al (2017) Bassoon controls presynaptic autophagy through Atg5. Neuron 93:897–913.e7. doi:10.1016/j.neuron.2017.01.026
Chinnadurai G (2009) The transcriptional corepressor CtBP: a foe of multiple tumor suppressors. Cancer Res 69:731–734. doi:10.1158/0008-5472.CAN-08-3349
Deguchi-Tawarada M, Inoue E, Takao-Rikitsu E et al (2004) CAST2: identification and characterization of a protein structurally related to the presynaptic cytomatrix protein CAST. Genes Cells Devoted Mol Cell Mech 9:15–23
Wang Y, Liu X, Biederer T, Südhof TC (2002) A family of RIM-binding proteins regulated by alternative splicing: implications for the genesis of synaptic active zones. Proc Natl Acad Sci U S A 99:14464–14469. doi:10.1073/pnas.182532999
Ohtsuka T, Takao-Rikitsu E, Inoue E et al (2002) Cast: a novel protein of the cytomatrix at the active zone of synapses that forms a ternary complex with RIM1 and munc13-1. J Cell Biol 158:577–590. doi:10.1083/jcb.200202083
Takao-Rikitsu E, Mochida S, Inoue E et al (2004) Physical and functional interaction of the active zone proteins, CAST, RIM1, and bassoon, in neurotransmitter release. J Cell Biol 164:301–311. doi:10.1083/jcb.200307101
Ko J, Na M, Kim S et al (2003) Interaction of the ERC family of RIM-binding proteins with the liprin-alpha family of multidomain proteins. J Biol Chem 278:42377–42385. doi:10.1074/jbc.M307561200
Monier S, Jollivet F, Janoueix-Lerosey I, et al. (2002) Characterization of novel Rab6-interacting proteins involved in endosome-to-TGN transport. Traffic (Copenhagen, Denmark) 3:289–297.
Ko J, Yoon C, Piccoli G et al (2006) Organization of the presynaptic active zone by ERC2/CAST1-dependent clustering of the tandem PDZ protein syntenin-1. J Neurosci Off J Soc Neurosci 26:963–970. doi:10.1523/JNEUROSCI.4475-05.2006
Kaeser PS, Deng L, Chávez AE et al (2009) ELKS2alpha/CAST deletion selectively increases neurotransmitter release at inhibitory synapses. Neuron 64:227–239. doi:10.1016/j.neuron.2009.09.019
Dieck S, Specht D, Strenzke N et al (2012) Deletion of the presynaptic scaffold CAST reduces active zone size in rod photoreceptors and impairs visual processing. J Neurosci 32:12192–12203. doi:10.1523/JNEUROSCI.0752-12.2012
Liu C, Bickford LS, Held RG et al (2014) The active zone protein family ELKS supports Ca2+ influx at nerve terminals of inhibitory hippocampal neurons. J Neurosci Off J Soc Neurosci 34:12289–12303. doi:10.1523/JNEUROSCI.0999-14.2014
Kiyonaka S, Nakajima H, Takada Y et al (2012) Physical and functional interaction of the active zone protein CAST/ERC2 and the -subunit of the voltage-dependent Ca2+ channel. J Biochem 152:149–159. doi:10.1093/jb/mvs054
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. doi:10.7554/eLife.14862
Wagh DA, Rasse TM, Asan E et al (2006) Bruchpilot, a protein with homology to ELKS/CAST, is required for structural integrity and function of synaptic active zones in Drosophila. Neuron 49:833–844. doi:10.1016/j.neuron.2006.02.008
Kittel RJ, Wichmann C, Rasse TM et al (2006) Bruchpilot promotes active zone assembly, Ca2+ channel clustering, and vesicle release. Science 312:1051–1054. doi:10.1126/science.1126308
Deken SL, Vincent R, Hadwiger G et al (2005) Redundant localization mechanisms of RIM and ELKS in Caenorhabditis elegans. J Neurosci 25:5975–5983. doi:10.1523/JNEUROSCI.0804-05.2005
Dai Y, Taru H, Deken SL et al (2006) SYD-2 Liprin-α organizes presynaptic active zone formation through ELKS. Nat Neurosci 9:1479–1487. doi:10.1038/nn1808
Wang Y, Okamoto M, Schmitz F et al (1997) Rim is a putative Rab3 effector in regulating synaptic-vesicle fusion. Nature 388:593–598. doi:10.1038/41580
Wang Y, Südhof TC (2003) Genomic definition of RIM proteins: evolutionary amplification of a family of synaptic regulatory proteins. Genomics 81:126–137
Mittelstaedt T, Schoch S (2007) Structure and evolution of RIM-BP genes: identification of a novel family member. Gene 403:70–79. doi:10.1016/j.gene.2007.08.004
Coppola T, Magnin-Luthi S, Perret-Menoud V et al (2001) Direct interaction of the Rab3 effector RIM with Ca2+channels, SNAP-25, and synaptotagmin. J Biol Chem 276:32756–32762. doi:10.1074/jbc.M100929200
Gandini MA, Felix R (2012) Functional interactions between voltage-gated Ca2+ channels and Rab3-interacting molecules (RIMs): new insights into stimulus–secretion coupling. Biochim Biophys Acta Biomembr 1818:551–558. doi:10.1016/j.bbamem.2011.12.011
Schoch S, Castillo PE, Jo T et al (2002) RIM1alpha forms a protein scaffold for regulating neurotransmitter release at the active zone. Nature 415:321–326. doi:10.1038/415321a
Castillo PE, Schoch S, Schmitz F et al (2002) RIM1α is required for presynaptic long-term potentiation. Nature 415:327–330. doi:10.1038/415327a
Powell CM, Schoch S, Monteggia L et al (2004) The presynaptic active zone protein RIM1alpha is critical for normal learning and memory. Neuron 42:143–153
Deng L, Kaeser PS, Xu W, Südhof TC (2011) RIM proteins activate vesicle priming by reversing autoinhibitory homodimerization of Munc13. Neuron 69:317–331. doi:10.1016/j.neuron.2011.01.005
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. doi:10.1016/j.neulet.2008.08.026
Koushika SP, Richmond JE, Hadwiger G et al (2001) A post-docking role for active zone protein rim. Nat Neurosci 4:997–1005. doi:10.1038/nn732
Han Y, Babai N, Kaeser P et al (2015) RIM1 and RIM2 redundantly determine Ca2+ channel density and readily releasable pool size at a large hindbrain synapse. J Neurophysiol 113:255–263. doi:10.1152/jn.00488.2014
Kaeser PS, Deng L, Wang Y et al (2011) RIM proteins tether Ca2+ channels to presynaptic active zones via a direct PDZ-domain interaction. Cell 144:282–295. doi:10.1016/j.cell.2010.12.029
Graf ER, Valakh V, Wright CM et al (2012) RIM promotes calcium channel accumulation at active zones of the Drosophila neuromuscular junction. J Neurosci Off J Soc Neurosci 32:16586–16596. doi:10.1523/JNEUROSCI.0965-12.2012
Lu J, Machius M, Dulubova I et al (2006) Structural basis for a Munc13–1 homodimer to Munc13–1/RIM heterodimer switch. PLoS Biol 4:e192. doi:10.1371/journal.pbio.0040192
Hibino H, Pironkova R, Onwumere O et al (2002) RIM binding proteins (RBPs) couple Rab3-interacting molecules (RIMs) to voltage-gated Ca(2+) channels. Neuron 34:411–423
Acuna C, Liu X, Gonzalez A, Südhof TC (2015) RIM-BPs mediate tight coupling of action potentials to Ca2+−triggered neurotransmitter release. Neuron 87:1234–1247. doi:10.1016/j.neuron.2015.08.027
Acuna C, Liu X, Südhof TC (2016) How to make an active zone: unexpected universal functional redundancy between RIMs and RIM-BPs. Neuron 91:792–807. doi:10.1016/j.neuron.2016.07.042
Muller M, Liu KSY, Sigrist SJ, Davis GW (2012) RIM controls homeostatic plasticity through modulation of the readily-releasable vesicle pool. J Neurosci 32:16574–16585. doi:10.1523/JNEUROSCI.0981-12.2012
Müller M, Genç Ö, Davis GW (2015) RIM-binding protein links synaptic homeostasis to the stabilization and replenishment of high release probability vesicles. Neuron 85:1056–1069. doi:10.1016/j.neuron.2015.01.024
Wang Y, Sugita S, Sudhof TC (2000) The RIM/NIM family of neuronal C2 domain proteins. Interactions with Rab3 and a new class of Src homology 3 domain proteins. J Biol Chem 275:20033–20044. doi:10.1074/jbc.M909008199
Grauel MK, Maglione M, Reddy-Alla S et al (2016) RIM-binding protein 2 regulates release probability by fine-tuning calcium channel localization at murine hippocampal synapses. Proc Natl Acad Sci U S A 113:11615–11620. doi:10.1073/pnas.1605256113
Serra-Pagès C, Kedersha NL, Fazikas L et al (1995) The LAR transmembrane protein tyrosine phosphatase and a coiled-coil LAR-interacting protein co-localize at focal adhesions. EMBO J 14:2827–2838
Serra-Pagès C, Medley QG, Tang M et al (1998) Liprins, a family of LAR transmembrane protein-tyrosine phosphatase-interacting proteins. J Biol Chem 273:15611–15620
Taru H, Jin Y (2011) The liprin homology domain is essential for the homomeric interaction of SYD-2/liprin- protein in presynaptic assembly. J Neurosci 31:16261–16268. doi:10.1523/JNEUROSCI.0002-11.2011
Ko J, Na M, Kim S et al (2003) Interaction of the ERC family of RIM-binding proteins with the liprin—family of multidomain proteins. J Biol Chem 278:42377–42385. doi:10.1074/jbc.M307561200
Dai Y, Taru H, Deken SL et al (2006) SYD-2 liprin-alpha organizes presynaptic active zone formation through ELKS. Nat Neurosci 9:1479–1487. doi:10.1038/nn1808
Astigarraga S, Hofmeyer K, Farajian R, Treisman JE (2010) Three Drosophila liprins interact to control synapse formation. J Neurosci Off J Soc Neurosci 30:15358–15368. doi:10.1523/JNEUROSCI.1862-10.2010
Olsen O, Moore KA, Fukata M et al (2005) Neurotransmitter release regulated by a MALS–liprin-α presynaptic complex. J Cell Biol 170:1127–1134. doi:10.1083/jcb.200503011
Kalla S, Stern M, Basu J et al (2006) Molecular dynamics of a presynaptic active zone protein studied in Munc13-1-enhanced yellow fluorescent protein knock-in mutant mice. J Neurosci 26:13054–13066. doi:10.1523/JNEUROSCI.4330-06.2006
Tsuriel S, Fisher A, Wittenmayer N et al (2009) Exchange and redistribution dynamics of the cytoskeleton of the active zone molecule bassoon. J Neurosci 29:351–358. doi:10.1523/JNEUROSCI.4777-08.2009
Spangler SA, Jaarsma D, De Graaff E et al (2011) Differential expression of liprin-α family proteins in the brain suggests functional diversification. J Comp Neurol 519:3040–3060. doi:10.1002/cne.22665
Wei Z, Zheng S, Spangler SA et al (2011) Liprin-mediated large signaling complex organization revealed by the liprin-α/CASK and liprin-α/liprin-β complex structures. Mol Cell 43:586–598. doi:10.1016/j.molcel.2011.07.021
Spangler SA, Schmitz SK, Kevenaar JT et al (2013) Liprin-α2 promotes the presynaptic recruitment and turnover of RIM1/CASK to facilitate synaptic transmission. J Cell Biol 201:915–928. doi:10.1083/jcb.201301011
Zhen M, Jin Y (1999) The liprin protein SYD-2 regulates the differentiation of presynaptic termini in C. elegans. Nature 401:371–375. doi:10.1038/43886
Augustin I, Rosenmund C, Südhof TC, Brose N (1999) Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles. Nature 400:457–461. doi:10.1038/22768
Junge HJ, Rhee J-S, Jahn O et al (2004) Calmodulin and Munc13 form a Ca2+ sensor/effector complex that controls short-term synaptic plasticity. Cell 118:389–401. doi:10.1016/j.cell.2004.06.029
Kawabe H, Mitkovski M, Kaeser PS et al (2017) ELKS1 localizes the synaptic vesicle priming protein bMunc13-2 to a specific subset of active zones. J Cell Biol 216:1143–1161. doi:10.1083/jcb.201606086
Brose N, Hofmann K, Hata Y, Südhof TC (1995) Mammalian homologues of Caenorhabditis elegans unc-13 gene define novel family of C2-domain proteins. J Biol Chem 270:25273–25280
Koch H, Hofmann K, Brose N (2000) Definition of Munc13-homology-domains and characterization of a novel ubiquitously expressed Munc13 isoform. Biochem J 349:247–253
Basu J, Shen N, Dulubova I et al (2005) A minimal domain responsible for Munc13 activity. Nat Struct Mol Biol 12:1017–1018. doi:10.1038/nsmb1001
Ma C, Li W, Xu Y, Rizo J (2011) Munc13 mediates the transition from the closed syntaxin–Munc18 complex to the SNARE complex. Nat Struct Mol Biol 18:542–549. doi:10.1038/nsmb.2047
Betz A, Thakur P, Junge HJ et al (2001) Functional interaction of the active zone proteins Munc13-1 and RIM1 in synaptic vesicle priming. Neuron 30:183–196
Dulubova I, Lou X, Lu J et al (2005) A Munc13/RIM/Rab3 tripartite complex: from priming to plasticity? EMBO J 24:2839–2850. doi:10.1038/sj.emboj.7600753
Wang X, Hu B, Zieba A et al (2009) A protein interaction node at the neurotransmitter release site: domains of aczonin/piccolo, bassoon, CAST, and rim converge on the N-terminal domain of Munc13-1. J Neurosci Off J Soc Neurosci 29:12584–12596. doi:10.1523/JNEUROSCI.1255-09.2009
Nakata T, Terada S, Hirokawa N (1998) Visualization of the dynamics of synaptic vesicle and plasma membrane proteins in living axons. J Cell Biol 140:659–674
Friedman HV, Bresler T, Garner CC, Ziv NE (2000) Assembly of new individual excitatory synapses: time course and temporal order of synaptic molecule recruitment. Neuron 27:57–69
Shapira M, Zhai RG, Dresbach T et al (2003) Unitary assembly of presynaptic active zones from piccolo-bassoon transport vesicles. Neuron 38:237–252
Dresbach T, Torres V, Wittenmayer N et al (2006) Assembly of active zone precursor vesicles: obligatory trafficking of presynaptic cytomatrix proteins bassoon and piccolo via a trans-Golgi compartment. J Biol Chem 281:6038–6047
Fairless R, Masius H, Rohlmann A et al (2008) Polarized targeting of neurexins to synapses is regulated by their C-terminal sequences. J Neurosci 28:12969–12981. doi:10.1523/JNEUROSCI.5294-07.2008
Su Q, Cai Q, Gerwin C et al (2004) Syntabulin is a microtubule-associated protein implicated in syntaxin transport in neurons. Nat Cell Biol 6:941–953. doi:10.1038/ncb1169
Cai Q, Pan P-Y, Sheng Z-H (2007) Syntabulin-kinesin-1 family member 5B-mediated axonal transport contributes to activity-dependent presynaptic assembly. J Neurosci 27:7284–7296. doi:10.1523/JNEUROSCI.0731-07.2007
Sabo SL, Gomes RA, McAllister AK (2006) Formation of presynaptic terminals at predefined sites along axons. J Neurosci 26:10813–10825. doi:10.1523/JNEUROSCI.2052-06.2006
Bury LA, Sabo SL (2011) Coordinated trafficking of synaptic vesicle and active zone proteins prior to synapse formation. Neural Dev 6:24. doi:10.1186/1749-8104-6-24
Fernandez F, Torres V, Zamorano P (2010) An evolutionarily conserved mechanism for presynaptic trapping. Cell Mol Life Sci 67:1751–1754
Dresbach T, Hempelmann A, Spilker C et al (2003) Functional regions of the presynaptic cytomatrix protein bassoon: significance for synaptic targeting and cytomatrix anchoring. Mol Cell Neurosci 23:279–291
Jose M, Nair DK, Altrock WD et al (2008) Investigating interactions mediated by the presynaptic protein bassoon in living cells by Foerster’s resonance energy transfer and fluorescence lifetime imaging microscopy. Biophys J 94:1483–1496. doi:10.1529/biophysj.107.111674
Siebert M, Böhme MA, Driller JH et al (2015) A high affinity RIM-binding protein/Aplip1 interaction prevents the formation of ectopic axonal active zones. elife. doi:10.7554/eLife.06935
Nieratschker V, Schubert A, Jauch M et al (2009) Bruchpilot in ribbon-like axonal agglomerates, behavioral defects, and early death in SRPK79D kinase mutants of Drosophila. PLoS Genet 5:e1000700. doi:10.1371/journal.pgen.1000700
Johnson EL, Fetter RD, Davis GW (2009) Negative regulation of active zone assembly by a newly identified SR protein kinase. PLoS Biol 7:e1000193. doi:10.1371/journal.pbio.1000193
Klassen MP, Wu YE, Maeder CI 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. doi:10.1016/j.neuron.2010.04.033
Dai Z, Peng HB (1996) Dynamics of synaptic vesicles in cultured spinal cord neurons in relationship to synaptogenesis. Mol Cell Neurosci 7:443–452. doi:10.1006/mcne.1996.0032
Bernstein BW, DeWit M, Bamburg JR (1998) Actin disassembles reversibly during electrically induced recycling of synaptic vesicles in cultured neurons. Brain Res Mol Brain Res 53:236–251
Zhang W, Benson DL (2001) Stages of synapse development defined by dependence on F-actin. J Neurosci Off J Soc Neurosci 21:5169–5181
Nelson JC, Stavoe AKH, Colón-Ramos DA (2013) The actin cytoskeleton in presynaptic assembly. Cell Adhes Migr 7:379–387. doi:10.4161/cam.24803
Wang XH, Zheng JQ, Poo MM (1996) Effects of cytochalasin treatment on short-term synaptic plasticity at developing neuromuscular junctions in frogs. J Physiol:187–195
Kim CH, Lisman JE (1999) A role of actin filament in synaptic transmission and long-term potentiation. J Neurosci Off J Soc Neurosci 19:4314–4324
Bleckert A, Photowala H, Alford S (2012) Dual pools of actin at presynaptic terminals. J Neurophysiol 107:3479–3492. doi:10.1152/jn.00789.2011
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. doi:10.1038/nn.2991
Fujimoto K, Shibasaki T, Yokoi N et al (2002) Piccolo, a Ca2+ sensor in pancreatic beta-cells. Involvement of cAMP-GEFII.Rim2. Piccolo complex in cAMP-dependent exocytosis. J Biol Chem 277:50497–50502. doi:10.1074/jbc.M210146200
Waites CL, Garner CC (2011) Presynaptic function in health and disease. Trends Neurosci 34:326–337. doi:10.1016/j.tins.2011.03.004
Dickins EM, Salinas PC (2013) Wnts in action: from synapse formation to synaptic maintenance. Front Cell Neurosci 7:162. doi:10.3389/fncel.2013.00162
Inestrosa NC, Varela-Nallar L (2014) Wnt signaling in the nervous system and in Alzheimer’s disease. J Mol Cell Biol 6:64–74. doi:10.1093/jmcb/mjt051
Varela-Nallar L, Alfaro IE, Serrano FG et al (2010) Wingless-type family member 5A (Wnt-5a) stimulates synaptic differentiation and function of glutamatergic synapses. Proc Natl Acad Sci 107:21164–21169. doi:10.1073/pnas.1010011107
Inestrosa NC, Arenas E (2010) Emerging roles of Wnts in the adult nervous system. Nat Rev Neurosci 11:77–86. doi:10.1038/nrn2755
Budnik V, Salinas PC (2011) Wnt signaling during synaptic development and plasticity. Curr Opin Neurobiol 21:151–159. doi:10.1016/j.conb.2010.12.002
Cerpa W, Gambrill A, Inestrosa NC, Barria A (2011) Regulation of NMDA-receptor synaptic transmission by Wnt signaling. J Neurosci Off J Soc Neurosci 31:9466–9471. doi:10.1523/JNEUROSCI.6311-10.2011
Oliva CA, Vargas JY, Inestrosa NC (2013) Wnts in adult brain: from synaptic plasticity to cognitive deficiencies. Front Cell Neurosci 7:224. doi:10.3389/fncel.2013.00224
Toledo EM, Colombres M, Inestrosa NC (2008) Wnt signaling in neuroprotection and stem cell differentiation. Prog Neurobiol 86:281–296. doi:10.1016/j.pneurobio.2008.08.001
Logan CY, Nusse R (2004) The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 20:781–810. doi:10.1146/annurev.cellbio.20.010403.113126
Gordon MD, Nusse R (2006) Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors. J Biol Chem 281:22429–22433. doi:10.1074/jbc.R600015200
Habas R, Kato Y, He X (2001) Wnt/Frizzled activation of rho regulates vertebrate gastrulation and requires a novel formin homology protein Daam1. Cell 107:843–854
Rosso SB, Sussman D, Wynshaw-Boris A, Salinas PC (2005) Wnt signaling through Dishevelled, Rac and JNK regulates dendritic development. Nat Neurosci 8:34–42. doi:10.1038/nn1374
Rosso SB, Inestrosa NC (2013) WNT signaling in neuronal maturation and synaptogenesis. Front Cell Neurosci 7:103. doi:10.3389/fncel.2013.00103
Inestrosa NC, Montecinos-Oliva C, Fuenzalida M (2012) Wnt signaling: role in Alzheimer disease and schizophrenia. J NeuroImmune Pharmacol 7:788–807. doi:10.1007/s11481-012-9417-5
Lucas FR, Salinas PC (1997) WNT-7a induces axonal remodeling and increases synapsin I levels in cerebellar neurons. Dev Biol 192:31–44. doi:10.1006/dbio.1997.8734
Hall AC, Lucas FR, Salinas PC (2000) Axonal remodeling and synaptic differentiation in the cerebellum is regulated by WNT-7a signaling. Cell 100:525–535
Cerpa W, Godoy JA, Alfaro I et al (2007) Wnt-7a modulates the synaptic vesicle cycle and synaptic transmission in hippocampal neurons. J Biol Chem 283:5918–5927. doi:10.1074/jbc.M705943200
Ahmad-Annuar A, Ciani L, Simeonidis I et al (2006) Signaling across the synapse: a role for Wnt and dishevelled in presynaptic assembly and neurotransmitter release. J Cell Biol 174:127–139. doi:10.1083/jcb.200511054
Varela-Nallar L, Grabowski CP, Alfaro IE et al (2009) Role of the Wnt receptor Frizzled-1 in presynaptic differentiation and function. Neural Dev 4:41. doi:10.1186/1749-8104-4-41
Liu W, Sato A, Khadka D et al (2008) Mechanism of activation of the formin protein Daam1. Proc Natl Acad Sci U S A 105:210–215. doi:10.1073/pnas.0707277105
Young KG, Copeland JW (2010) Formins in cell signaling. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1803:183–190. doi:10.1016/j.bbamcr.2008.09.017
Bateman J, Van Vactor D (2001) The trio family of guanine-nucleotide-exchange factors: regulators of axon guidance. J Cell Sci 114:1973–1980
Mabb AM, Ehlers MD (2010) Ubiquitination in postsynaptic function and plasticity. Annu Rev Cell Dev Biol 26:179–210. doi:10.1146/annurev-cellbio-100109-104129
Fernández-Chacón R, Wölfel M, Nishimune H et al (2004) The synaptic vesicle protein CSP alpha prevents presynaptic degeneration. Neuron 42:237–251
Wheeler TC, Chin L-S, Li Y et al (2002) Regulation of synaptophysin degradation by mammalian homologues of seven in absentia. J Biol Chem 277:10273–10282. doi:10.1074/jbc.M107857200
Iwata A, Christianson JC, Bucci M et al (2005) Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation. Proc Natl Acad Sci U S A 102:13135–13140. doi:10.1073/pnas.0505801102
Pandey UB, Nie Z, Batlevi Y et al (2007) HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 447:859–863. doi:10.1038/nature05853
Kumar A, Bodhinathan K, Foster TC (2009) Susceptibility to calcium dysregulation during brain aging. Front Aging Neurosci 1:2. doi:10.3389/neuro.24.002.2009
Bezprozvanny I (2009) Calcium signaling and neurodegenerative diseases. Trends Mol Med 15:89–100. doi:10.1016/j.molmed.2009.01.001
Yu X, Malenka RC (2003) β-catenin is critical for dendritic morphogenesis. Nat Neurosci 6:1169–1177. doi:10.1038/nn1132
Chen J, Park CS, Tang S-J (2006) Activity-dependent synaptic Wnt release regulates hippocampal long term potentiation. J Biol Chem 281:11910–11916. doi:10.1074/jbc.M511920200
Wayman GA, Impey S, Marks D et al (2006) Activity-dependent dendritic arborization mediated by CaM-kinase I activation and enhanced CREB-dependent transcription of Wnt-2. Neuron 50:897–909. doi:10.1016/j.neuron.2006.05.008
Gogolla N, Galimberti I, Deguchi Y, Caroni P (2009) Wnt signaling mediates experience-related regulation of synapse numbers and mossy fiber connectivities in the adult hippocampus. Neuron 62:510–525. doi:10.1016/j.neuron.2009.04.022
Purro SA, Dickins EM, Salinas PC (2012) The secreted Wnt antagonist Dickkopf-1 is required for amyloid β-mediated synaptic loss. J Neurosc Off J Soc Neurosci 32:3492–3498. doi:10.1523/JNEUROSCI.4562-11.2012
Chen C-M, Orefice LL, Chiu S-L et al (2017) Wnt5a is essential for hippocampal dendritic maintenance and spatial learning and memory in adult mice. Proc Natl Acad Sci U S A 114:E619–E628. doi:10.1073/pnas.1615792114
Acknowledgments
This work was supported by grants from the Basal Center of Excellence in Aging and Regeneration (CONICYT-PFB 12/2007) and FONDECYT (No. 1160724) to N. C. Inestrosa. V. Torres, a Research Associate of CARE. We also thank the Sociedad Química y Minera de Chile (SQM) for a special grant on “The Effects of Lithium on Health and Disease.”
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing Interests
The authors declare that they have no conflicts of interest.
Rights and permissions
About this article
Cite this article
Torres, V.I., Inestrosa, N.C. Vertebrate Presynaptic Active Zone Assembly: a Role Accomplished by Diverse Molecular and Cellular Mechanisms. Mol Neurobiol 55, 4513–4528 (2018). https://doi.org/10.1007/s12035-017-0661-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12035-017-0661-9