Loss of Skywalker Reveals Synaptic Endosomes as Sorting Stations for Synaptic Vesicle Proteins

Uytterhoeven, Valerie; Kuenen, Sabine; Kasprowicz, Jarosław; Miśkiewicz, Katarzyna; Verstreken, Patrik

doi:10.1016/j.cell.2011.02.039

Cited by 200 publications

(285 citation statements)

References 75 publications

Supporting

Mentioning

276

Contrasting

Unclassified

Order By: Relevance

“…This has been observed in mutants for tbc1D24-a GAP for Rab35. A high rate of turnover of synaptic vesicle proteins in these mutants is seen to increase neurotransmitter release (Uytterhoeven et al 2011;Fernandes et al 2014).…”

Section: Discussionmentioning

confidence: 99%

A Presynaptic Regulatory System Acts Transsynaptically via Mon1 to Regulate Glutamate Receptor Levels in Drosophila

et al. 2015

View full text Add to dashboard Cite

Mon1 is an evolutionarily conserved protein involved in the conversion of Rab5 positive early endosomes to late endosomes through the recruitment of Rab7. We have identified a role for Drosophila Mon1 in regulating glutamate receptor levels at the larval neuromuscular junction. We generated mutants in Dmon1 through P-element excision. These mutants are short-lived with strong motor defects. At the synapse, the mutants show altered bouton morphology with several small supernumerary or satellite boutons surrounding a mature bouton; a significant increase in expression of GluRIIA and reduced expression of Bruchpilot. Neuronal knockdown of Dmon1 is sufficient to increase GluRIIA levels, suggesting its involvement in a presynaptic mechanism that regulates postsynaptic receptor levels. Ultrastructural analysis of mutant synapses reveals significantly smaller synaptic vesicles. Overexpression of vglut suppresses the defects in synaptic morphology and also downregulates GluRIIA levels in Dmon1 mutants, suggesting that homeostatic mechanisms are not affected in these mutants. We propose that DMon1 is part of a presynaptically regulated transsynaptic mechanism that regulates GluRIIA levels at the larval neuromuscular junction.

show abstract

Section: Discussionmentioning

confidence: 99%

A Presynaptic Regulatory System Acts Transsynaptically via Mon1 to Regulate Glutamate Receptor Levels in Drosophila

et al. 2015

View full text Add to dashboard Cite

show abstract

“…One such mutant, shibire, encodes dynamin, a GTPase required late in the process of endocytosis and synaptic vesicle recycling that is responsible for fission of the vesicle from the membrane (van der Bliek and Meyerowrtz 1991). The shibire mutant shi ts1 is a temperature-sensitive missense mutation in the GTPase domain of the protein, and when flies are heated to the restrictive temperature (29°) and stimulated, nerve terminals become completely depleted of synaptic vesicles, paralyzing the flies (Koenig et al 1983;van der Bliek and Meyerowrtz 1991). Ultrastructural analysis of the depleted nerve terminals shows the presynaptic membrane filled with clathrin-coated pits corresponding to vesicles stuck at the late stage of endocytosis, waiting to be pinched off by dynamin .…”

mentioning

confidence: 99%

Disruption of Endocytosis with the Dynamin Mutantshibirets1Suppresses Seizures inDrosophila

et al. 2015

View full text Add to dashboard Cite

One challenge in modern medicine is to control epilepsies that do not respond to currently available medications. Since seizures consist of coordinated and high-frequency neural activity, our goal was to disrupt neurotransmission with a synaptic transmission mutant and evaluate its ability to suppress seizures. We found that the mutant shibire, encoding dynamin, suppresses seizure-like activity in multiple seizure-sensitive Drosophila genotypes, one of which resembles human intractable epilepsy in several aspects. Because of the requirement of dynamin in endocytosis, increased temperature in the shi ts1 mutant causes impairment of synaptic vesicle recycling and is associated with suppression of the seizure-like activity. Additionally, we identified the giant fiber neuron as critical in the seizure circuit and sufficient to suppress seizures. Overall, our results implicate mutant dynamin as an effective seizure suppressor, suggesting that targeting or limiting the availability of synaptic vesicles could be an effective and general method of controlling epilepsy disorders.

show abstract

“…While the role of Rab6 in membrane trafficking is well established, very few GAPs or GEFs for Rab6 have been identified; thus their physiological importance is largely unknown. The physiological roles of RabGAPs were addressed only recently in flies (Houalla et al 2010;Uytterhoeven et al 2011) and worms (Chotard et al 2010). In those cases, removing the function of the RabGAPs produced phenotypes almost identical to those of removing the relevant Rabs, showing the fundamental roles of RabGAPs in modulating Rab functions.…”

mentioning

confidence: 99%

The Jaw of the Worm: GTPase-activating Protein EAT-17 Regulates Grinder Formation in Caenorhabditis elegans

et al. 2013

View full text Add to dashboard Cite

Constitutive transport of cellular materials is essential for cell survival. Although multiple small GTPase Rab proteins are required for the process, few regulators of Rabs are known. Here we report that EAT-17, a novel GTPase-activating protein (GAP), regulates RAB-6.2 function in grinder formation in Caenorhabditis elegans. We identified EAT-17 as a novel RabGAP that interacts with RAB-6.2, a protein that presumably regulates vesicle trafficking between Golgi, the endoplasmic reticulum, and plasma membrane to form a functional grinder. EAT-17 has a canonical GAP domain that is critical for its function. RNA interference against 25 confirmed and/or predicted RABs in C. elegans shows that RNAi against rab-6.2 produces a phenotype identical to eat-17. A directed yeast twohybrid screen using EAT-17 as bait and each of the 25 RAB proteins as prey identifies RAB-6.2 as the interacting partner of EAT-17, confirming that RAB-6.2 is a specific substrate of EAT-17. Additionally, deletion mutants of rab-6.2 show grinder defects identical to those of eat-17 loss-of-function mutants, and both RAB-6.2 and EAT-17 are expressed in the terminal bulb of the pharynx where the grinder is located. Collectively, these results suggest that EAT-17 is a specific GTPase-activating protein for RAB-6.2. Based on the conserved function of Rab6 in vesicular transport, we propose that EAT-17 regulates the turnover rate of RAB-6.2 activity in cargo trafficking for grinder formation. C ELLS constitutively transport newly synthesized proteins, lipids, and other molecules to their periphery through vesicle trafficking. As the process is conserved from yeast to humans, it is essential for the function and survival of cells. Rab GTPases are small GTP binding proteins that regulate the transport of vesicles between different compartments of the cell (Zerial and McBride 2001;Jordens et al. 2005;Grosshans et al. 2006). Rab6's are localized to Golgi membranes to mark and target both anterograde cargos from Golgi to post-Golgi compartments (such as the plasma membrane) and retrograde cargos from early/recycling endosomes to Golgi and the endoplasmic reticulum (Jasmin et al. 1992;Martinez et al. 1994Martinez et al. , 1997Girod et al. 1999;Opdam et al. 2000;Del Nery et al. 2006). For fast turnover, Rabs require guanine nucleotide exchange factors (Rab GEFs) for activation and GTPase-activating proteins (Rab GAPs) to turn off activity (Grosshans et al. 2006). While the role of Rab6 in membrane trafficking is well established, very few GAPs or GEFs for Rab6 have been identified; thus their physiological importance is largely unknown. The physiological roles of RabGAPs were addressed only recently in flies (Houalla et al. 2010;Uytterhoeven et al. 2011) and worms (Chotard et al. 2010). In those cases, removing the function of the RabGAPs produced phenotypes almost identical to those of removing the relevant Rabs, showing the fundamental roles of RabGAPs in modulating Rab functions. Currently, the only identified GAP for Rab6 is GAPCenA in humans,...

show abstract

Loss of Skywalker Reveals Synaptic Endosomes as Sorting Stations for Synaptic Vesicle Proteins

Cited by 200 publications

References 75 publications

A Presynaptic Regulatory System Acts Transsynaptically via Mon1 to Regulate Glutamate Receptor Levels in Drosophila

A Presynaptic Regulatory System Acts Transsynaptically via Mon1 to Regulate Glutamate Receptor Levels in Drosophila

Disruption of Endocytosis with the Dynamin Mutantshibirets1Suppresses Seizures inDrosophila

The Jaw of the Worm: GTPase-activating Protein EAT-17 Regulates Grinder Formation in Caenorhabditis elegans

Contact Info

Product

Resources

About