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• W2022921920 abstract "Presynaptic differentiation is a remarkable cellular event. At the correct time and place, a motile growth cone is transformed into a stable synaptic contact. In the case of en passent synapse formation, a similar transformation occurs at specific locations along an axon length. In both instances, this transformation requires spatially and temporally controlled changes in cell shape that are driven by cytoskeletal rearrangement. During this process, synaptic proteins are recruited to the forming synapse and are rapidly assembled into an intercellular junction that is capable of high-fidelity neurotransmission. While we are gaining remarkable insight into the mechanisms of postsynaptic differentiation, the molecules that stimulate presynaptic differentiation remain obscure. Even at the vertebrate neuromuscular junction (NMJ), arguably the most well-characterized synapse in the nervous system, the factors that drive presynaptic differentiation are unknown (reviewed by 13Sanes J.R Lichtman J.W Annu. Rev. Neurosci. 1999; 22: 389-442Crossref PubMed Scopus (1229) Google Scholar). Agrin and neuregulin are released from the presynaptic motoneuron and act through MuSK and erbB kinases, respectively, to induce the clustering and synthesis of postsynaptic acetylcholine receptors (reviewed by 13Sanes J.R Lichtman J.W Annu. Rev. Neurosci. 1999; 22: 389-442Crossref PubMed Scopus (1229) Google Scholar). However, similar pathways involved in presynaptic differentiation have not been identified. Agrin is also synthesized in muscle, and although presynaptic differentiation is impaired in an agrin knockout mouse, this effect appears to be secondary to impaired postsynaptic differentiation. Apparently, additional postsynaptic factors are necessary to induce presynaptic differentiation (1Burgess R.W Nguyen Q.T Son Y.J Lichtman J.W Sanes J.R Neuron. 1998; 23: 33-44Abstract Full Text Full Text PDF Scopus (203) Google Scholar). Two recent papers by 5Hall A.C Lucas F.R Salinas P.C Cell. 2000; 100: 525-535Abstract Full Text Full Text PDF PubMed Scopus (591) Google Scholar and 14Scheiffele, P., Fan, J., Choih, J., Fetter, R., and Serafini, T. (2000). Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons. Cell 101, 657–669.Google Scholar have generated a significant advance in our understanding of the mechanisms that regulate presynaptic differentiation. 5Hall A.C Lucas F.R Salinas P.C Cell. 2000; 100: 525-535Abstract Full Text Full Text PDF PubMed Scopus (591) Google Scholar implicate WNT7a as a target-derived, secreted synaptogenic signal. WNT7a is a member of a large family of secreted WNT proteins that have previously been demonstrated to participate in a variety of developmental events such as cell fate decisions, cell polarity, and patterning events. Sheiffele et al. (2000) demonstrate that neuroligin-mediated signaling is sufficient to drive synapse formation in vitro. This work implicates neuroligin-neurexin signaling as a contact-dependent event that can drive synapse formation. Together, these results identify a potential sequence of signaling events that initiate and promote presynaptic differentiation in the CNS. 5Hall A.C Lucas F.R Salinas P.C Cell. 2000; 100: 525-535Abstract Full Text Full Text PDF PubMed Scopus (591) Google Scholar exploit a pontine explant/granule cell coculture system to demonstrate that the secreted signaling molecule WNT7a functions during synaptogenesis at the mossy fiber–granule cell synapse. Granule cells occupy the innermost layer of the cerebral cortex and are synapsed upon by mossy fibers that originate from the pontine nuclei as well as other somatosensory centers. Several features of in vivo synapse formation at the mossy fiber–granule cell synapse are recapitulated in this culture system, including a characteristic enlargement of the mossy fiber growth cone that precedes synapse formation. Granule cells normally express the secreted signaling molecule WNT7a during the period of synapse formation in the cerebellum from P12 to P22. In their recent study, 5Hall A.C Lucas F.R Salinas P.C Cell. 2000; 100: 525-535Abstract Full Text Full Text PDF PubMed Scopus (591) Google Scholar report several experiments demonstrating that WNT7a is involved in axonal remodeling events that may represent the initial events of synapse formation including growth cone spreading and cytoskeletal rearrangement. WNT7a, when presented to mossy fiber axons in either a cell surface or soluble form, causes axon spreading and an increase in the size and complexity of the growth cone. These effects of WNT7a mimic the effects of ganglion cell conditioned media, suggesting that WNT7a is a factor secreted by ganglion cells that induces this process in vivo. Furthermore, the effects of granule cell conditioned media can be blocked by the addition of a WNT signaling antagonist, sFRP-1. A canonical signaling pathway has been established downstream of WNT/Wingless signaling. WNT signals are transduced via frizzled receptors (fz) to activate an intracellular signaling cascade that represses the activity of glycogen synthase 3β kinase (GSK3β). GSK3β is highly expressed in the central nervous system and has been implicated in the regulation of the microtubule cytoskeleton via phosphorylation of microtubule-associated proteins such as MAP1B (4Goold R.G Owen R Gordon-Weeks P.R J. Cell Sci. 1999; 112: 3373-3384Crossref PubMed Google Scholar). 5Hall A.C Lucas F.R Salinas P.C Cell. 2000; 100: 525-535Abstract Full Text Full Text PDF PubMed Scopus (591) Google Scholar implicate WNT signaling via GSK3β in the regulation of the axonal and growth cone microtubule cytoskeleton. In the cerebellar culture system, inhibition of GSK3β with lithium induces axon spreading and growth cone enlargement that are similar to those observed in response to WNT7a (5Hall A.C Lucas F.R Salinas P.C Cell. 2000; 100: 525-535Abstract Full Text Full Text PDF PubMed Scopus (591) Google Scholar). The cytoskeletal remodeling induced by WNT7a and GSK3β is associated with a reorganization of the microtuble cytoskeleton. Microtubules become unbundled near the end of the axon shaft, and microtubules in the growth cone become spread, forming complex microtubule arrays. The authors also observe an accumulation of synapsin I immunoreactivity that occurs in parallel with WNT7a- and GSK3β-mediated cytoskeletal rearrangement. This supports the hypothesis that the observed WNT-mediated effects are initial steps in the process of synapse formation. Thus, WNT7a appears to be a target-derived synaptogenic factor in the mouse cerebellum (Figure 1). Remarkable parallels between synapse formation and growth cone motility have been observed in studies examining microtubule dynamics. Microtubule dynamic instability is considered necessary for growth cone motility, during which the microtubules attain a splayed conformation (16Tanaka E Ho T Kirschner M.W J. Cell Biol. 1995; 128: 139-155Crossref PubMed Scopus (301) Google Scholar, 3Dent E.W Callaway J.L Szebenyi G Baas P.W Kalil K J. Neurosci. 1999; 19: 8894-8908Crossref PubMed Google Scholar). Microtubules at a stalled growth cone, however, adopt a different conformation that is nearly identical to that adopted during synapse formation and synaptic growth (3Dent E.W Callaway J.L Szebenyi G Baas P.W Kalil K J. Neurosci. 1999; 19: 8894-8908Crossref PubMed Google Scholar, 12Roos J Hummel T Ng N Klambt C Davis G.W Neuron. 2000; 26: 371-382Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar). Microtubules within a stalled growth cone are observed to form a loop of stable microtubules that is disrupted upon resumed growth cone motility (3Dent E.W Callaway J.L Szebenyi G Baas P.W Kalil K J. Neurosci. 1999; 19: 8894-8908Crossref PubMed Google Scholar). Nearly identical microtubule loops are observed at newly formed synaptic connections both in vitro and in vivo (12Roos J Hummel T Ng N Klambt C Davis G.W Neuron. 2000; 26: 371-382Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar). GSK3β signaling downstream of WNT7a has been hypothesized to contribute to the regulation of the microtubule cytoskeleton via phosphorylation of microtubule-associated proteins such as MAP1B. A role for MAP-dependent regulation of the microtubule cytoskeleton during synapse formation and synaptic growth has been implicated in a variety of systems in vitro and has recently been demonstrated in vivo at the Drosophila NMJ (18Togel M Wiche G Propst F J. Cell Biol. 1998; 143: 695-707Crossref PubMed Scopus (133) Google Scholar, 12Roos J Hummel T Ng N Klambt C Davis G.W Neuron. 2000; 26: 371-382Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar). In Drosophila, the recently isolated MAP1B-like protein Futsch associates with microtubules in vivo and in vitro and is necessary for microtubule organization at the growth cone and synapse (6Hummel T Krukkert K Roos J Davis G.W Klambt C Neuron. 2000; 26: 357-370Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar, 12Roos J Hummel T Ng N Klambt C Davis G.W Neuron. 2000; 26: 371-382Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar). A genetic analysis demonstrates that Futsch is necessary for both synapse formation and synaptic growth. Thus, a critical element of synapse formation, the transformation of growth cone shape and motility, may represent one end of the continuum of cytoskeletal dynamics that normally occurs during growth cone motility. WNT signaling appears to impact this basic process during synapse formation. 14Scheiffele, P., Fan, J., Choih, J., Fetter, R., and Serafini, T. (2000). Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons. Cell 101, 657–669.Google Scholar demonstrate that contact-mediated intercellular signaling via a neuroligin-neurexin junction is sufficient to drive synapse formation in vivo at the pontine–granule cell synapse. The neurexins, because of their many different isoforms, have been hypothesized to establish molecular diversity that may be important for establishing specific synapse formation across diverse synapse types in the CNS (10Missler M Fernandez-Chacon R Südhof T.C Neurochemistry. 1998; 71: 1339-1347Crossref PubMed Scopus (137) Google Scholar). While the subcellular localization of neurexins within central neurons remains to be determined, neuroligin-1 is present postsynaptically at central synapses and has been shown to be a β-neurexin ligand (15Song J.Y Ichtchenko K Südhof T.C Brose N Proc. Natl. Acad. Sci. USA. 1999; 96: 1100-1105Crossref PubMed Scopus (545) Google Scholar). Three neuroligins have been identified in rat, and now two neuroligins have been identified in mouse (14Scheiffele, P., Fan, J., Choih, J., Fetter, R., and Serafini, T. (2000). Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons. Cell 101, 657–669.Google Scholar). All of the known neuroligins possess an extracellular domain that shares homology with acetylcholinesterase, though this domain does not have enzymatic activity (15Song J.Y Ichtchenko K Südhof T.C Brose N Proc. Natl. Acad. Sci. USA. 1999; 96: 1100-1105Crossref PubMed Scopus (545) Google Scholar, 14Scheiffele, P., Fan, J., Choih, J., Fetter, R., and Serafini, T. (2000). Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons. Cell 101, 657–669.Google Scholar). A transsynaptic protein scaffold has been assembled around the neurexin-neuroligin asymmetric junction that is hypothesized to participate in the organization of the synapse. This model assumes an asymmetric junction with presynaptic neurexin and postsynaptic neuroligin. Presynaptic neurexin interacts with an evolutionarily conserved protein complex consisting of the modular adaptor proteins CASK, MINT1, and Veli (2Butz S Okamoto M Südhof T.C Cell. 1998; 94: 773-782Abstract Full Text Full Text PDF PubMed Scopus (466) Google Scholar). Significantly, both CASK and MINT1 are associated biochemically with a presynaptic calcium channel subunit (8Maximov A Südhof T.C Bezprozvanny I Biol. Chem. 1999; 274: 24453-24456Crossref Scopus (259) Google Scholar). The CASK SH3 domain has been shown to interact with a proline-rich sequence in the presynaptic calcium channel. The carboxyl termini of the α1a and α1b calcium channel subunits also bind to the first PDZ domain of MINT1. Thus, a transsynaptic protein complex is linked biochemically to presynaptic calcium channels (8Maximov A Südhof T.C Bezprozvanny I Biol. Chem. 1999; 274: 24453-24456Crossref Scopus (259) Google Scholar). This transsynaptic protein complex is hypothesized to organize the localization or function of presynaptic calcium channels and potentially other constituents of the synapse. A role for this complex in protein localization is supported by genetic analysis of an analogous lin-10/lin-2/lin-7 protein complex in C. elegans. The lin-10/lin-2/lin-7 complex is necessary and sufficient for basolateral localization of the EGF receptor tyrosine kinase let-23 and for the postsynaptic localization of glutamate receptors (7Kaech S.M Whitfield C.W Kim S.K Cell. 1998; 94: 761-771Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar, 11Rongo C Whitfield C.W Rodal A Kim S.K Kaplan J.M Cell. 1998; 94: 751-759Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar). Until now, however, there has been no experimental evidence supporting a role for the neurexin-neuroligin transsynaptic complex in either synapse formation or modulation. The experiments described by 14Scheiffele, P., Fan, J., Choih, J., Fetter, R., and Serafini, T. (2000). Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons. Cell 101, 657–669.Google Scholar demonstrate that mouse neuroligin 1 and neuroligin 2 are able to initiate synapse formation in vitro. The authors utilize a culture system of pontine explants cocultured with HEK293 cells (some experiments are successfully repeated with other nonneuronal cell types of different origin, including COS cells). This system allows the authors to manipulate the expression of neuroligin 1 and 2 in the nonneuronal target cell. The authors utilize this system to great advantage. When pontine axons contact HEK293 cells expressing a GFP control vector, there is no evidence of synapse formation. However, HEK293 cells expressing neuroligin-1 or neuroligin-2 initiate de novo synapse formation by pontine axons onto these nonneuronal cells. Synapse formation is assessed by several criteria. Synapsin, synaptotagmin, and synaptophysin, all molecular markers for synaptic connections in the cerebellum, accumulate in axons at sites of contact with neuroligin-expressing cells (Figure 2). The authors provide ultrastructural evidence supporting the formation of synaptic connections, and they provide evidence for depolarization-dependent vesicle exocytosis and endocytosis at these new synaptic sites. These data argue strongly that synapse formation is induced by neuroligin expression by the nonneuronal HEK293 cells. The authors utilize their culture system to argue that neuroligin-neurexin signaling is also necessary for synapse formation. A deletion analysis demonstrates that the synaptogenic activity of neuroligin is due primarily to the presence of the acetylcholinesterase-homologous extracellular domain, while other portions of the extracellular region and the cytoplasmic domain are not necessary. Domain swap experiments further demonstrate that sequences specific to the neuroligin acetylcholinesterase-like domain are required for this activity. Finally, the authors effectively compete the synaptogenic activity of neuroligin by adding soluble neurexin to their cultures. The addition of soluble neurexin not only inhibits synapse formation of pontine axons contacting neuroligin-expressing HEK293 cells, but also inhibits synapse formation between pontine axons and cocultured cerebellar granular cells, the in vivo targets of these axons. These data provide the first evidence of a cell contact–mediated signaling event that is sufficient to drive either presynaptic differentiation or synapse formation in the CNS (Figure 1B). The in vitro evidence for both WNT and neuroligin function demonstrate that these molecules are sufficient to induce discrete events during synapse formation. Each paper also provides evidence indicating that these signaling events are also necessary in vitro. Scheiffele et al. demonstrate that synapse formation between pontine axons and their normal granule cell targets can be inhibited by the addition of soluble neurexin. One interpretation is that the soluble neurexin competes with an endogenous neuroligin-neurexin interaction and prevents synapse formation (synapse formation is reduced by nearly 80%). Similarly, Hall et al. show that a WNT signaling antagonist blocks the characteristic cytoskeletal and cell shape changes that are induced by ganglion cell conditioned media. Genetic data, however, argue against a required role for either WNTs or neuroligins in the process of synaptogenesis in vivo. Synapse formation is merely delayed in the WNT7a knockout mouse, demonstrating that WNT7a is not genetically required for synapse formation in vivo. Similarly, the neuroligin knockout mouse is remarkably healthy. A common explanation for such genetic data is that synapse formation utilizes additional factors that have overlapping or redundant function. Multiple WNTs, for example, are expressed in the cerebellum, and redundancy has been suggested for WNT signaling in other tissues (9McMahon A.P Bradley A Cell. 1990; 62: 1073-1085Abstract Full Text PDF PubMed Scopus (1241) Google Scholar). Without assuming redundant molecular function, how is it possible to reconcile the observation that neuroligin and WNT7a appear necessary and sufficient to induce presynaptic differentiation in vitro and yet appear to be nearly dispensable in knockout mice? One possible view is that presynaptic differentiation may not be a transformation that requires discrete inductive signals such as those observed for agrin and neuregulin during postsynaptic differentiation at the NMJ (13Sanes J.R Lichtman J.W Annu. Rev. Neurosci. 1999; 22: 389-442Crossref PubMed Scopus (1229) Google Scholar). Rather, the events that induce presynaptic differentiation in the CNS may require the integration of many opposing signals, including those that promote and inhibit growth cone motility. Thus, in vitro, neuroligin expression could be sufficient to induce presynaptic differentiation because very few growth cone motility–promoting factors are present to compete with experimentally supplied neuroligin. A similar argument could be made regarding the observations that neuroligin and WNT7a appear necessary for synapse formation in vitro. This model might also explain the subtle phenotypes of neuroligin and WNT7a knockout mice. Synapse formation might be delayed, but not prevented, because only one piece of a complex signaling menagerie is missing and this perturbation is not sufficient to block synapse formation. Such an explanation draws upon a current understanding of axon guidance that requires the integration of attractive and repulsive cues to generate directed motility (17Tessier-Lavigne M Goodman C.S Science. 1996; 274: 1123-1133Crossref PubMed Scopus (2689) Google Scholar). In the end, the function of WNT7a and neuroligin may not be genetically necessary, but they appear have discrete and important functions during synapse formation. Presynaptic differentiation requires a complex transformation, and it can be achieved with remarkable speed following target contact (19Xie Z.P Poo M.-M Proc. Natl. Acad. Sci. USA. 1986; 83: 7069-7073Crossref PubMed Scopus (174) Google Scholar). The sequential function of WNTs and neurexins might impact the speed and fidelity of presynaptic differentiation. WNT7a may speed the process of synapse formation by inducing cytoskeletal remodeling and inducing the accumulation of synaptic proteins when the axon nears its appropriate granule cell target but doing so before target contact is established. Similarly, “synaptogenic” molecules such as neuroligins might rapidly induce presynaptic assembly once appropriate target contact is established. Assembly of the presynaptic release machinery may be achieved via the formation of a presynaptic protein scaffold that includes MINT1, CASK, and Veli, already implicated in synaptic protein localization and calcium channel binding (11Rongo C Whitfield C.W Rodal A Kim S.K Kaplan J.M Cell. 1998; 94: 751-759Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 8Maximov A Südhof T.C Bezprozvanny I Biol. Chem. 1999; 274: 24453-24456Crossref Scopus (259) Google Scholar). Given the diversity of synaptic types in the CNS, how much diversity is necessary to establish specific patterns of synaptic connectivity? The word is still out. One view of presynaptic differentiation is that diverse target recognition molecules are necessary to induce specific synaptic connectivity. These target recognition molecules may include the remarkable number of potentially different neurexins. Alternatively, synaptic specificity could be achieved through the integration of multiple signals, including growth cone motility factors, growth cone stability factors, and synaptogenic factors. Synapse formation would ensue at the time and place when the balance of signal integration is tipped toward presynaptic differentiation; a process that might include but not necessarily require a target recognition element. It is now possible to imagine a sequence of basic molecular events that underlies the induction of presynaptic differentiation. Signaling via a secreted signaling molecule such as WNT7a initiates the process of synapse formation at a distance, potentially initiating the cytoskeletal rearrangments necessary for the transition from a growth cone to a stable synapse. Target recognition and signaling via an asymmetric neuroligin-neurexin junction may then nucleate the rapid assembly of the presynaptic release machinery. Together, these data represent a glimpse at hitherto elusive signals that drive presynaptic differentiation." @default.
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• W2022921920 title "The Making of a Synapse" @default.
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