aex-3 Encodes a Novel Regulator of Presynaptic Activity in C. elegans

Iwasaki, Kouichi; Staunton, Jane; Saifee, Owais; Nonet, Michael L.; Thomas, James H.

doi:10.1016/s0896-6273(00)80302-5

Cited by 138 publications

(155 citation statements)

References 54 publications

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“…Both the immunohistochemical defect and aldicarb resistance of y250 and y251 were linked to rol-6, suggesting they were rab-3 lesions, whereas defects in y255 animals were unlinked to rol-6. y255 was demonstrated to be an allele of aex-3 (Iwasaki et al, 1997). rab-3 was positioned between bli-2 and dpy-10 by three-factor mapping.…”

Section: Methodsmentioning

confidence: 99%

Caenorhabditis elegans rab-3Mutant Synapses Exhibit Impaired Function and Are Partially Depleted of Vesicles

et al. 1997

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Rab molecules regulate vesicular trafficking in many different exocytic and endocytic transport pathways in eukaryotic cells. In neurons, rab3 has been proposed to play a crucial role in regulating synaptic vesicle release. To elucidate the role of rab3 in synaptic transmission, we isolated and characterized Caenorhabditis elegans rab-3 mutants. Similar to the mouse rab3A mutants, these mutants survived and exhibited only mild behavioral abnormalities. In contrast to the mouse mutants, synaptic transmission was perturbed in these animals. Extracellular electrophysiological recordings revealed that synaptic transmission in the pharyngeal nervous system was impaired. Furthermore, rab-3 animals were resistant to the acetylcholinesterase inhibitor aldicarb, suggesting that cholinergic transmission was generally depressed. Last, synaptic vesicle populations were redistributed in rab-3 mutants. In motor neurons, vesicle populations at synapses were depleted to 40% of normal levels, whereas in intersynaptic regions of the axon, vesicle populations were elevated. On the basis of the morphological defects at neuromuscular junctions, we postulate that RAB-3 may regulate recruitment of vesicles to the active zone or sequestration of vesicles near release sites.

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Section: Methodsmentioning

confidence: 99%

Caenorhabditis elegans rab-3Mutant Synapses Exhibit Impaired Function and Are Partially Depleted of Vesicles

et al. 1997

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“…Pharyngeal pumping and aldicarb sensitivity were tested as described previously , and snt-1(md290) represent null alleles based on molecular, genetic, and immunohistochemical criteria (Nonet et al, 1993Schaefer et al, 2000). ae x -3( y255) behaves as a strong loss-of-f unction allele (Iwasaki et al, 1997). However, the null phenotype has not been strictly defined.…”

Section: Methodsmentioning

confidence: 99%

Rabphilin Potentiates SolubleN-Ethylmaleimide Sensitive Factor Attachment Protein Receptor Function Independently of rab3

2001

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Rabphilin, a putative rab effector, interacts specifically with the GTP-bound form of the synaptic vesicle-associated protein rab3a. In this study, we define in vivo functions for rabphilin through the characterization of mutants that disrupt the Caenorhabditis elegans rabphilin homolog. The mutants do not display the general synaptic defects associated with rab3 lesions, as assayed at the pharmacological, physiological, and ultrastructural level. However, rabphilin mutants exhibit severe lethargy in the absence of mechanical stimulation. Furthermore, rabphilin mutations display strong synergistic interactions with hypomorphic lesions in the syntaxin, synaptosomal-associated protein of 25 kDa, and synaptobrevin soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) genes; double mutants were nonresponsive to mechanical stimulation. These synergistic interactions were independent of rab3 function and were not observed in rab3-SNARE double mutants. Our data reveal rab3-independent functions for rabphilin in the potentiation of SNARE function.

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“…Association of the Rab protein with the vesicle membrane often requires the activity of the GEF protein (Pfeffer, 2005). In particular, RAB-3 association with synaptic vesicles requires AEX-3 (Iwasaki et al, 1997). Thus, we tested whether RAB-27 is also mislocalized in aex-3 mutants.…”

Section: Aex-3 Regulates Both Rab-3 and Rab-27mentioning

confidence: 99%

“…Surprisingly, more dramatic phenotypes are found in Rab3 GEF knockout mice, which exhibit a marked reduction in evoked release that is not seen in the Rab3 knockout mice (Wada et al, 1997;Tanaka et al, 2001;Yamaguchi et al, 2002). Similarly, C. elegans aex-3 (Rab3 GEF homologue) mutants have more severe synaptic transmission defects than rab-3 mutants and exhibit defects in the defecation motor program not seen in rab-3 mutants (Iwasaki et al, 1997). These findings suggest that the Rab3 exchange factor homologue, AEX-3, may regulate another closely related Rab besides RAB-3.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Synaptic Transmission by RAB-3 and RAB-27 inCaenorhabditis elegans

Mahoney

Liu

Itoh

et al. 2006

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159

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Rab small GTPases are involved in the transport of vesicles between different membranous organelles. RAB-3 is an exocytic Rab that plays a modulatory role in synaptic transmission. Unexpectedly, mutations in the Caenorhabditis elegans RAB-3 exchange factor homologue, aex-3, cause a more severe synaptic transmission defect as well as a defecation defect not seen in rab-3 mutants. We hypothesized that AEX-3 may regulate a second Rab that regulates these processes with RAB-3. We found that AEX-3 regulates another exocytic Rab, RAB-27. Here, we show that C. elegans RAB-27 is localized to synapse-rich regions pan-neuronally and is also expressed in intestinal cells. We identify aex-6 alleles as containing mutations in rab-27. Interestingly, aex-6 mutants exhibit the same defecation defect as aex-3 mutants. aex-6; rab-3 double mutants have behavioral and pharmacological defects similar to aex-3 mutants. In addition, we demonstrate that RBF-1 (rabphilin) is an effector of RAB-27. Therefore, our work demonstrates that AEX-3 regulates both RAB-3 and RAB-27, that both RAB-3 and RAB-27 regulate synaptic transmission, and that RAB-27 potentially acts through its effector RBF-1 to promote soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) function. INTRODUCTIONNeurotransmitter release is accomplished by the fusion of neurotransmitter-filled synaptic vesicles at the presynaptic nerve terminal. This process occurs through a series of highly regulated steps that include synaptic vesicle transport, docking/tethering, priming, fusion, endocytosis, recycling, and neurotransmitter refilling (Sudhof, 2004). Several genes have been assigned roles in the various steps of the synaptic vesicle cycle. Rab3 (termed RAB-3 in Caenorhabditis elegans), a member of the Rab family of small GTPases, regulates synaptic transmission, possibly through the docking, priming, or fusion steps Schluter et al., 2004).Rabs act in a variety of cell types and regulate vesicular transport between organelles. Rabs cycle on and off membranes via a GTP-dependent mechanism (Zerial and McBride, 2001). Rab activity is regulated by two proteins, which act in an antagonistic manner. The guanine nucleotide exchange factor (GEF) exchanges GTP for GDP, and the GTPase activating protein activates the intrinsic GTPase activity of a Rab (Bernards, 2003). GDP bound Rabs are held off of the membrane by a GDP dissociation inhibitor (Wu et al., 1996). The GTP/membrane-bound form of Rabs typically binds to a variety of effectors that regulate particular steps of membrane transport and cell signaling (Zerial and McBride, 2001;Spang, 2004).Rab3 was once thought to play a central role in regulating release. However, recent work has shown that a quadruple knockout of all four isoforms of Rab3 in mice only results in a 30% reduction in evoked synaptic response (Schluter et al., 2004). This is consistent with work in C. elegans showing that mutations in the single rab-3 gene cause only mild defects in synaptic transmission . Surprisingly, more dramatic phe...

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aex-3 Encodes a Novel Regulator of Presynaptic Activity in C. elegans

Cited by 138 publications

References 54 publications

Caenorhabditis elegans rab-3Mutant Synapses Exhibit Impaired Function and Are Partially Depleted of Vesicles

Caenorhabditis elegans rab-3Mutant Synapses Exhibit Impaired Function and Are Partially Depleted of Vesicles

Rabphilin Potentiates SolubleN-Ethylmaleimide Sensitive Factor Attachment Protein Receptor Function Independently of rab3

Regulation of Synaptic Transmission by RAB-3 and RAB-27 inCaenorhabditis elegans

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