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• W2040478973 abstract "Many types of synapses have highly characteristic shapes and tightly regulated distributions of active zones, parameters that are important to the function of neuronal circuits. The development of terminal arborizations must therefore include mechanisms to regulate the spacing of terminals, the frequency of branching, and the distribution and density of release sites. At present, however, the mechanisms that control these features remain obscure. Here, we report the development of supernumerary or “satellite” boutons in a variety of endocytic mutants at the Drosophila neuromuscular junction. Mutants in endophilin, synaptojanin, dynamin, AP180, and synaptotagmin all show increases in supernumerary bouton structures. These satellite boutons contain releasable vesicles and normal complements of synaptic proteins that are correctly localized within terminals. Interestingly, however, synaptojanin terminals have more active zones per unit of surface area and more dense bodies (T-bars) within these active zones, which may in part compensate for reduced transmission per active zone. The altered structural development of the synapse is selectively encountered in endocytosis mutants and is not observed when synaptic transmission is reduced by mutations in glutamate receptors or when synaptic transmission is blocked by tetanus toxin. We propose that endocytosis plays a critical role in sculpting the structure of synapses, perhaps through the endocytosis of unknown regulatory signals that organize morphogenesis at synaptic terminals. Many types of synapses have highly characteristic shapes and tightly regulated distributions of active zones, parameters that are important to the function of neuronal circuits. The development of terminal arborizations must therefore include mechanisms to regulate the spacing of terminals, the frequency of branching, and the distribution and density of release sites. At present, however, the mechanisms that control these features remain obscure. Here, we report the development of supernumerary or “satellite” boutons in a variety of endocytic mutants at the Drosophila neuromuscular junction. Mutants in endophilin, synaptojanin, dynamin, AP180, and synaptotagmin all show increases in supernumerary bouton structures. These satellite boutons contain releasable vesicles and normal complements of synaptic proteins that are correctly localized within terminals. Interestingly, however, synaptojanin terminals have more active zones per unit of surface area and more dense bodies (T-bars) within these active zones, which may in part compensate for reduced transmission per active zone. The altered structural development of the synapse is selectively encountered in endocytosis mutants and is not observed when synaptic transmission is reduced by mutations in glutamate receptors or when synaptic transmission is blocked by tetanus toxin. We propose that endocytosis plays a critical role in sculpting the structure of synapses, perhaps through the endocytosis of unknown regulatory signals that organize morphogenesis at synaptic terminals. At the neuromuscular junctions (NMJs) of third instar Drosophila larvae, the morphology of each synapse onto a particular body wall muscle is highly stereotyped [1Atwood H.L. Govind C.K. Wu C.F. Differential ultrastructure of synaptic terminals on ventral longitudinal abdominal muscles in Drosophila larvae.J. Neurobiol. 1993; 24: 1008-1024Crossref PubMed Scopus (316) Google Scholar] and results from a combination of embryonic development and postembryonic growth [2Schuster C.M. Davis G.W. Fetter R.D. Goodman C.S. Genetic dissection of structural and functional components of synaptic plasticity. II. Fasciclin II controls presynaptic structural plasticity.Neuron. 1996; 17: 655-667Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar]. Within these terminals, active zones obey a minimum spacing function, even in mutants that have altered morphology of the bouton [3Meinertzhagen I.A. Govind C.K. Stewart B.A. Carter J.M. Atwood H.L. Regulated spacing of synapses and presynaptic active zones at larval neuromuscular junctions in different genotypes of the flies Drosophila and Sarcophaga.J. Comp. Neurol. 1998; 393: 482-492Crossref PubMed Scopus (51) Google Scholar]. While studying mutations in the proteins of the synaptic endocytic apparatus, we have noted that there are consistent changes in the structure of these synapses. Endophilin is a protein that accelerates clathrin-mediated endocytosis [4Dickman D.K. Horne J.A. Meinertzhagen I.A. Schwarz T.L. A slowed classical pathway rather than kiss-and-run mediates endocytosis at synapses lacking synaptojanin and endophilin.Cell. 2005; 123: 521-533Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar] and interacts with several other proteins in the endocytic pathway [5Slepnev V.I. De Camilli P. Accessory factors in clathrin-dependent synaptic vesicle endocytosis.Nat. Rev. Neurosci. 2000; 1: 161-172Crossref PubMed Scopus (419) Google Scholar, 6Ringstad N. Nemoto Y. De Camilli P. The SH3p4/Sh3p8/SH3p13 protein family: binding partners for synaptojanin and dynamin via a Grb2-like Src homology 3 domain.Proc. Natl. Acad. Sci. USA. 1997; 94: 8569-8574Crossref PubMed Scopus (320) Google Scholar]. We noted that the neuromuscular junctions of third instar larvae homozygous for endoΔ4, a null allele of endophilin [7Verstreken P. Kjaerulff O. Lloyd T.E. Atkinson R. Zhou Y. Meinertzhagen I.A. Bellen H.J. Endophilin mutations block clathrin-mediated endocytosis but not neurotransmitter release.Cell. 2002; 109: 101-112Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar], contained numerous satellite boutons, i.e., small supernumerary boutons protruding from the primary terminal axis (Figure 1). This phenotype strongly resembled that of dap160 mutants [8Marie B. Sweeney S.T. Poskanzer K.E. Roos J. Kelly R.B. Davis G.W. Dap160/intersectin scaffolds the periactive zone to achieve high-fidelity endocytosis and normal synaptic growth.Neuron. 2004; 43: 207-219Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, 9Koh T.W. Verstreken P. Bellen H.J. Dap160/intersectin acts as a stabilizing scaffold required for synaptic development and vesicle endocytosis.Neuron. 2004; 43: 193-205Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar]. The endoΔ4 phenotype was fully penetrant at all NMJs, but we chose to count satellite boutons of the single axon that innervates the middle of muscle 4 because of its relative simplicity and suitability for quantification [8Marie B. Sweeney S.T. Poskanzer K.E. Roos J. Kelly R.B. Davis G.W. Dap160/intersectin scaffolds the periactive zone to achieve high-fidelity endocytosis and normal synaptic growth.Neuron. 2004; 43: 207-219Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar]. We defined satellite boutons as small protrusions emanating from the primary axial branch of nerve terminals. Control larvae had very few satellite boutons (2.48 ± 0.33 per NMJ, mean ± SEM, n = 21), but there was a 10-fold increase in endoΔ4 mutants (30.8 ± 1.9, n = 25; Figures 1A and 1B). To control for the genetic background, we examined larvae homozygous for another allele, endo1, as well as endo1/endoΔ4 larvae; both had abundant supernumerary boutons (31.1 ± 2.2 and 30.5 ± 1.4 satellite boutons/synapse, n = 24 and 39; Figures 1C and 1D). At these synapses, the boutons remained confined to the region of the muscle that normally receives the innervation, but this region was now crowded by the overgrowth of small boutons. At the end of embryogenesis, no abnormalities were apparent in the endophilin mutants (data not shown). Therefore, the satellite boutons must arise during larval development, a period in which the NMJ expands extensively. To test whether the increase in satellite boutons was due to a lack of endophilin function in the nervous system or musculature and to ensure that this phenotype results specifically from a lack of endophilin, we expressed endophilin in the null mutant background with drivers specific for either neurons or muscles (see Supplemental Experimental Procedures available with this article online). Neuronal expression restored wild-type structure to these synapses (2.75 ± 0.50 satellite boutons/synapse, n = 24; Figure 1E), but expression in muscle did not (data not shown). Thus, the development of supernumerary bouton structures results from a lack of endophilin function in the nervous system. To determine the extent to which these satellite boutons were true synaptic endings, we characterized the expression and localization of both pre- and postsynaptic proteins in endophilin mutants. The synaptic vesicle proteins synaptotagmin and cysteine string protein were present at both satellite boutons and the main axial boutons (Figures 2A and 2C and data not shown). Similarly, expression of the postsynaptic marker discs large was associated with both satellite and axial contacts. As expected for a functional synapse, the active zone marker nc82 within the satellite boutons [10Wucherpfennig T. Wilsch-Brauninger M. Gonzalez-Gaitan M. Role of Drosophila Rab5 during endosomal trafficking at the synapse and evoked neurotransmitter release.J. Cell Biol. 2003; 161: 609-624Crossref PubMed Scopus (334) Google Scholar] was correctly juxtaposed to postsynaptic clusters of the essential glutamate receptor subunit DGluRIII [11Marrus S.B. Portman S.L. Allen M.J. Moffat K.G. DiAntonio A. Differential localization of glutamate receptor subunits at the Drosophila neuromuscular junction.J. Neurosci. 2004; 24: 1406-1415Crossref PubMed Scopus (222) Google Scholar] (Figures 2B and 2D). Therefore, despite the altered patterning of boutons at the NMJ, the numerous small varicosities in endo mutants have the predicted organization of a functional synaptic bouton. dap160 mutants were reported to have a mislocalization and/or instability of several endocytic proteins in synaptic terminals, so we were concerned that the synaptic overgrowth in endophilin mutants may be an indirect consequence of dap160 instability or mislocalization or perhaps instability of other synaptic proteins. Synaptojanin has already been shown to be mislocalized in endophilin mutants [12Verstreken P. Koh T.W. Schulze K.L. Zhai R.G. Hiesinger P.R. Zhou Y. Mehta S.Q. Cao Y. Roos J. Bellen H.J. Synaptojanin is recruited by endophilin to promote synaptic vesicle uncoating.Neuron. 2003; 40: 733-748Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar], but we found normal immunofluorescence levels and distributions of dap160 and dynamin in endophilin (Figures 2E–2G). Similarly, fasciclin II, a cell-surface protein important in synaptogenesis, was normal in endophilin terminals, as was the neuronal membrane marker HRP (Figure 2G). Interestingly, when we quantified the immunofluorescence levels of the active zone marker nc82, we found a significant increase in endophilin mutant terminals (1.39 ± 0.09 compared with controls, 1.0 ± 0.02 fluorescence units, p < 0.01; Figure 2G). This increase is likely to reflect an increase in the number of active zones and/or dense bodies per synapse. Indeed, we counted 65% more nc82 puncta at the muscle 4 synapse in endoΔ4 than in control w1118 larvae (323.8 ± 16.8 compared with 196.9 ± 11.2 per synapse; mean ± SEM, n = 17 and 23, p < 0.001). This is likely to be an underestimate of active zones, particularly in the mutant terminals, due to the inability to distinguish closely spaced puncta (see below). Thus, we determined that most endocytic proteins retain correct detectable distributions in endophilin mutants, but more active zones are present. Because both dap160 and endophilin mutants displayed satellite boutons, we considered whether mutants in synaptojanin (synj) also display this phenotype. Synaptojanin is an inositol phosphatase that is recruited by endophilin to endocytic sites to promote synaptic vesicle uncoating [12Verstreken P. Koh T.W. Schulze K.L. Zhai R.G. Hiesinger P.R. Zhou Y. Mehta S.Q. Cao Y. Roos J. Bellen H.J. Synaptojanin is recruited by endophilin to promote synaptic vesicle uncoating.Neuron. 2003; 40: 733-748Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar, 13McPherson P.S. Garcia E.P. Slepnev V.I. David C. Zhang X. Grabs D. Sossin W.S. Bauerfeind R. Nemoto Y. De Camilli P. A presynaptic inositol-5-phosphatase.Nature. 1996; 379: 353-357Crossref PubMed Scopus (476) Google Scholar, 14Schuske K.R. Richmond J.E. Matthies D.S. Davis W.S. Runz S. Rube D.A. van der Bliek A.M. Jorgensen E.M. Endophilin is required for synaptic vesicle endocytosis by localizing synaptojanin.Neuron. 2003; 40: 749-762Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar]. By using null alleles of synj [4Dickman D.K. Horne J.A. Meinertzhagen I.A. Schwarz T.L. A slowed classical pathway rather than kiss-and-run mediates endocytosis at synapses lacking synaptojanin and endophilin.Cell. 2005; 123: 521-533Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar], we found structural defects in synaptic growth similar to those seen in endo mutants, 12.2 ± 0.69 (mean ± SEM, n = 33) satellite boutons/synapse in synjLY/Df(2R)x58-7, compared with 3.1 ± 0.41 in controls (n = 25; Figures 3A, 3B, and 3L). This 4-fold increase was statistically significant (p < 0.001; Figure 3L) and could be rescued by presynaptic, but not postsynaptic, expression of a GFP-tagged synaptojanin transgene (2.86 ± 0.42 per synapse, n = 21; Figures 3C and 3L). Thus, as in endophilin and dap160, the defects result from the lack of neuronal expression of the endocytic protein. Synaptic transmission occurs at the neuromuscular junctions of both synj and endo mutants [4Dickman D.K. Horne J.A. Meinertzhagen I.A. Schwarz T.L. A slowed classical pathway rather than kiss-and-run mediates endocytosis at synapses lacking synaptojanin and endophilin.Cell. 2005; 123: 521-533Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar, 7Verstreken P. Kjaerulff O. Lloyd T.E. Atkinson R. Zhou Y. Meinertzhagen I.A. Bellen H.J. Endophilin mutations block clathrin-mediated endocytosis but not neurotransmitter release.Cell. 2002; 109: 101-112Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar, 12Verstreken P. Koh T.W. Schulze K.L. Zhai R.G. Hiesinger P.R. Zhou Y. Mehta S.Q. Cao Y. Roos J. Bellen H.J. Synaptojanin is recruited by endophilin to promote synaptic vesicle uncoating.Neuron. 2003; 40: 733-748Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar]. Do satellite boutons release and recycle synaptic vesicles or does all transmission in synj terminals occur at the axial boutons? To answer this directly, we used the lipophilic dye FM1-84 to monitor the synaptic vesicle cycle. Both control and synj terminals take up the dye when stimulated by electrical activity, because the absence of synaptojanin slows, but does not prevent, vesicle recycling and dye loading ([4Dickman D.K. Horne J.A. Meinertzhagen I.A. Schwarz T.L. A slowed classical pathway rather than kiss-and-run mediates endocytosis at synapses lacking synaptojanin and endophilin.Cell. 2005; 123: 521-533Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar]; Figures 3D and 3E). We loaded synj terminals with FM1-84 and found that the small satellite boutons, like the main axial boutons, could be loaded with dye and subsequently destained upon depolarization (Figure 3F and data not shown). Thus, these structures were capable of activity-dependent exocytosis and endocytosis of synaptic vesicles. Are satellite boutons a general property of endocytosis mutants? The best-studied endocytosis mutant in Drosophila is shibirets1, a temperature-sensitive mutation in the gene encoding dynamin. Dynamin is required for membrane fission, the pinching off of endocytosed vesicles from the plasma membrane. In shibire, at permissive temperatures (18°C and lower), vesicles are endocytosed normally, but at elevated temperatures (29°C and higher), endocytosis is blocked [15Koenig J.H. Ikeda K. Evidence for a presynaptic blockage of transmission in a temperature-sensitive mutant of Drosophila.J. Neurobiol. 1983; 14: 411-419Crossref PubMed Scopus (31) Google Scholar, 16Koenig J.H. Ikeda K. Disappearance and reformation of synaptic vesicle membrane upon transmitter release observed under reversible blockage of membrane retrieval.J. Neurosci. 1989; 9: 3844-3860Crossref PubMed Google Scholar]. shibire (shi) flies cannot survive for prolonged periods at the completely restrictive temperature of 29°C, but we could maintain them at an intermediate condition of 25°C, the temperature at which the other control and mutant stocks were raised. Under these conditions, shits1 larvae resembled synj mutants, with 12.5 ± 1.0 satellite boutons/synapse (n = 26, Figures 3H and 3L). As expected for this temperature-sensitive mutant, the phenotype did not arise at the permissive temperature of 18°C (4.0 ± 0.49 satellite boutons/synapse, n = 24; Figures 3G and 3L). lap/AP180 associates with the AP2 complex that recruits clathrin and regulates synaptic vesicle size [17Zhang B. Koh Y.H. Beckstead R.B. Budnik V. Ganetzky B. Bellen H.J. Synaptic vesicle size and number are regulated by a clathrin adaptor protein required for endocytosis.Neuron. 1998; 21: 1465-1475Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar, 18Ye W. Lafer E.M. Bacterially expressed F1–20/AP-3 assembles clathrin into cages with a narrow size distribution: implications for the regulation of quantal size during neurotransmission.J. Neurosci. Res. 1995; 41: 15-26Crossref PubMed Scopus (68) Google Scholar]. lap mutant larvae had 12.09 ± 1.13 satellite boutons/synapse (n = 23; Figures 3I and 3L), a 4-fold increase over wild-type. Finally, synaptotagmin, a calcium binding protein that promotes transmitter release, has also been shown to have a direct role in synaptic endocytosis, probably in part by recruiting the AP2 complex [19Poskanzer K.E. Marek K.W. Sweeney S.T. Davis G.W. Synaptotagmin I is necessary for compensatory synaptic vesicle endocytosis in vivo.Nature. 2003; 426: 559-563Crossref PubMed Scopus (213) Google Scholar, 20Zhang J.Z. Davletov B.A. Sudhof T.C. Anderson R.G. Synaptotagmin I is a high affinity receptor for clathrin AP-2: implications for membrane recycling.Cell. 1994; 78: 751-760Abstract Full Text PDF PubMed Scopus (428) Google Scholar, 21Nicholson-Tomishima K. Ryan T.A. Kinetic efficiency of endocytosis at mammalian CNS synapses requires synaptotagmin I.Proc. Natl. Acad. Sci. USA. 2004; 101: 16648-16652Crossref PubMed Scopus (103) Google Scholar]. In null mutants of synaptotagmin, we observed two differences in terminal morphology compared with wild-type. Axons were thinner and more highly branched than controls (Figure 3J). Also, there were more satellite boutons protruding from the branches, with 19.9 ± 1.1/synapse in sytAD4 (n = 31; Figures 3J and 3L). Thus, while the satellite boutons were consistent with the other endocytic mutants studied, the distinctive thinning and branching of axons might arise from the impairment of exocytosis in syt mutants. The satellite boutons of each endocytic mutant contained synaptic vesicle and active zone components (data not shown), indicating that, as in endophilin mutants, the supernumerary synapses were likely to be functional. All endocytosis mutations alter the release of neurotransmitter to some degree. The anatomical phenotype in these lines could therefore conceivably arise from decreases in synaptic transmission per se rather than defects specifically in endocytosis. To test this hypothesis, we diminished transmission with glutamate receptor mutations. Mutants in the glutamate receptor, DGluRIII, have reduced transmission at the larval NMJ that results from greatly decreased postsynaptic sensitivity [11Marrus S.B. Portman S.L. Allen M.J. Moffat K.G. DiAntonio A. Differential localization of glutamate receptor subunits at the Drosophila neuromuscular junction.J. Neurosci. 2004; 24: 1406-1415Crossref PubMed Scopus (222) Google Scholar]. Here, we observed wild-type bouton structure (3.1 ± 0.5 satellite boutons/synapse; n = 22; Figures 3K and 3L). Thus, reductions in synaptic strength are not sufficient to develop the phenotype observed in endocytic mutants. It remained possible that the satellite boutons arise secondarily from a decrease in release of either glutamate or of another molecule released by synaptic vesicles. We therefore compared the phenotype of the endocytosis mutants with the consequences of a complete block of presynaptic release, achieved through the expression of a tetanus toxin transgene (UAS-TNT-G; [22Sweeney S.T. Broadie K. Keane J. Niemann H. O'Kane C.J. Targeted expression of tetanus toxin light chain in Drosophila specifically eliminates synaptic transmission and causes behavioral defects.Neuron. 1995; 14: 341-351Abstract Full Text PDF PubMed Scopus (624) Google Scholar]). Widespread expression of this toxin is lethal and therefore prevents the analysis of the third instar NMJ. We found, however, that the rotund promoter (rn-GAL4; [23St Pierre S.E. Galindo M.I. Couso J.P. Thor S. Control of Drosophila imaginal disc development by rotund and roughened eye: differentially expressed transcripts of the same gene encoding functionally distinct zinc finger proteins.Development. 2002; 129: 1273-1281PubMed Google Scholar]) could drive expression of the transgene in a subset of ventral thoracic motor neurons throughout larval development, while maintaining the viability of the organism. Although tetanus toxin blocks all evoked release at the Drosophila NMJ [22Sweeney S.T. Broadie K. Keane J. Niemann H. O'Kane C.J. Targeted expression of tetanus toxin light chain in Drosophila specifically eliminates synaptic transmission and causes behavioral defects.Neuron. 1995; 14: 341-351Abstract Full Text PDF PubMed Scopus (624) Google Scholar], satellite boutons were not increased at these poisoned synapses relative to controls (2.4 ± 0.7 compared with 3.0 ± 0.8 in controls, n = 17 and 12; Figure S1). In endophilin mutants, these rotund-expressing thoracic motor neurons do produce satellite boutons (25.1 ± 4.1, n = 13; Figure S1), comparable to those previously quantified at abdominal muscle 4. Therefore, because complete blockade of synaptic transmission does not produce satellite boutons, whereas a comparatively subtle change in transmission in endophilin larvae does, the satellite boutons must arise as a direct consequence of the defect in endocytosis per se and not indirectly as a consequence of altered transmitter release. The anatomical defect observed at synapses of endocytosis mutants raised the possibility that there may be ultrastructural changes in the synaptic boutons as well. In three-dimensional reconstructions of synj third instar larval terminals on muscles 6 and 7, we observed changes in both active zones and dense bodies. Within the reconstructed segments of roughly equal length, the wild-type terminals had a total of 59 active zones while the synj terminals had a 22% increase, with 72 active zones (Figures 4A–4C). This correlates with what was observed at the light microscopic level in Figure 2. The mean area of an active zone appeared larger in wild-type (Figure 4C), but the difference was not significant (p = 0.11, t test), chiefly because of variation in the wild-type sample. The area occupied by a single dense body did not differ between genotypes (Figure 4C). However, the spacing density of synapses differed significantly, with active zones being about 50% more densely spaced over the plasma membrane of synj terminals than over wild-type ones (p = 0.013, t test; Figure 4D). The value of Ra, the mean nearest neighbor distances between the centers of active zones, did not differ significantly between terminals of the two genotypes (Figure 4C), however, despite the increased number of active zones and their increased density in synj terminals, indicating that active zones were arranged to maximize their spacing distance. Differences were also seen within active zone regions. In wild-type terminals, most active zones contain a single dense body. In synj terminals, however, there were more dense bodies per active zone on average (p = 0.001, t test; Figure 4D). This difference was attributable to more synj active zones having two dense bodies and fewer having one or none. Roughly 10% of synj active zones even had three dense bodies, a phenomenon not encountered in wild-type boutons. Commensurate with their increased number, the overall crowding of dense bodies was about twice as high in synj terminals as in wild-type ones (p = 0.013, t test), and the value for Ra was smaller (p = 0.0046, t test; Figure 4D), indicating that dense bodies in mutant terminals were spaced more closely to each other. The distribution of dense bodies, shown by the ratio Ra:Re (see Supplemental Data), was about 1 in the wild-type, indicating that normally dense bodies are randomly dispersed, whereas in synj terminals this ratio was less than 1, significantly different from wild-type (p = 0.011, t test). This indicates there is a tendency toward clustering dense bodies within individual mutant active zones (Figure 4D), although active zones themselves were randomly distributed in both synj and control. Thus, the structure of the neuromuscular junction is altered in synj mutants both in its overall architecture, by the presence of numerous satellite boutons, and also in its ultrastructure, through increases in the number and density of active zones and dense bodies. We have shown that a wide variety of endocytosis mutants produce 4–10 times more satellite boutons than wild-type controls and with comparable severity to that previously reported in dap160 mutants [8Marie B. Sweeney S.T. Poskanzer K.E. Roos J. Kelly R.B. Davis G.W. Dap160/intersectin scaffolds the periactive zone to achieve high-fidelity endocytosis and normal synaptic growth.Neuron. 2004; 43: 207-219Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, 9Koh T.W. Verstreken P. Bellen H.J. Dap160/intersectin acts as a stabilizing scaffold required for synaptic development and vesicle endocytosis.Neuron. 2004; 43: 193-205Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar]. The extent to which endocytosis was reduced in each genotype may differ. For example, synaptotagmin facilitates, but is not absolutely required for, endocytosis [19Poskanzer K.E. Marek K.W. Sweeney S.T. Davis G.W. Synaptotagmin I is necessary for compensatory synaptic vesicle endocytosis in vivo.Nature. 2003; 426: 559-563Crossref PubMed Scopus (213) Google Scholar, 21Nicholson-Tomishima K. Ryan T.A. Kinetic efficiency of endocytosis at mammalian CNS synapses requires synaptotagmin I.Proc. Natl. Acad. Sci. USA. 2004; 101: 16648-16652Crossref PubMed Scopus (103) Google Scholar, 24Schwarz T.L. Synaptotagmin promotes both vesicle fusion and recycling.Proc. Natl. Acad. Sci. USA. 2004; 101: 16401-16402Crossref PubMed Scopus (16) Google Scholar], and the rate of classical endocytosis is slowed, but not abolished, in null alleles of synj and endo [4Dickman D.K. Horne J.A. Meinertzhagen I.A. Schwarz T.L. A slowed classical pathway rather than kiss-and-run mediates endocytosis at synapses lacking synaptojanin and endophilin.Cell. 2005; 123: 521-533Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar]. Further, AP180 mutants retain the ability to endocytose synaptic vesicles, even though vesicle size is altered [17Zhang B. Koh Y.H. Beckstead R.B. Budnik V. Ganetzky B. Bellen H.J. Synaptic vesicle size and number are regulated by a clathrin adaptor protein required for endocytosis.Neuron. 1998; 21: 1465-1475Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar], and shibire was studied at a temperature that does not fully block endocytosis. Indeed, because endocytosis is essential for viability, the satellite boutons arise from the impairment rather than the abolition of endocytosis in each mutant studied. Endocytosis mutations have also been shown to alter bouton number at the neuromuscular junction [25Stimson D.T. Estes P.S. Smith M. Kelly L.E. Ramaswami M. A product of the Drosophila stoned locus regulates neurotransmitter release.J. Neurosci. 1998; 18: 9638-9649Crossref PubMed Google Scholar] and synaptic development in the giant fiber system [26Murphey R.K. Froggett S.J. Caruccio P. Shan-Crofts X. Kitamoto T. Godenschwege T.A. Targeted expression of shibire ts and semaphorin 1a reveals critical periods for synapse formation in the giant fiber of Drosophila.Development. 2003; 130: 3671-3682Crossref PubMed Scopus (19) Google Scholar]." @default.
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• W2040478973 date "2006-03-01" @default.
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• W2040478973 title "Altered Synaptic Development and Active Zone Spacing in Endocytosis Mutants" @default.
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• W2040478973 doi "https://doi.org/10.1016/j.cub.2006.02.058" @default.
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