Impaired dense core vesicle maturation in Caenorhabditis elegans mutants lacking Rab2

Despite a key role for dense core vesicles (DCVs) in neuronal function, there are major gaps in our understanding of DCV biogenesis. A genetic screen for Caenorhabditis elegans mutants with behavioral defects consistent with impaired DCV function yielded five mutations in UNC-108 (Rab2). A genetic a...

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Bibliographic Details
Published in:The Journal of cell biology 2009-09, Vol.186 (6), p.881-895
Main Authors: Edwards, Stacey L, Charlie, Nicole K, Richmond, Janet E, Hegermann, Jan, Eimer, Stefan, Miller, Kenneth G
Format: Article
Language:English
Subjects:
Animals
Axons - metabolism
Bacteria
Caenorhabditis elegans - enzymology
Caenorhabditis elegans - genetics
Caenorhabditis elegans - ultrastructure
Caenorhabditis elegans Proteins - genetics
Endosomes - enzymology
Evoked Potentials
Excitatory Postsynaptic Potentials
Genetics
Genotype
GTP-Binding Protein alpha Subunits - metabolism
Locomotion
Miniature Postsynaptic Potentials
Muscles - innervation
Mutation
Neurons - enzymology
Neurons - ultrastructure
Neuropeptides - metabolism
Peptides
Phenotype
Phosphatidylinositol Phosphates - metabolism
Protein Transport
Proteins
rab GTP-Binding Proteins - deficiency
rab GTP-Binding Proteins - genetics
rab2 GTP-Binding Protein - deficiency
rab2 GTP-Binding Protein - genetics
Secretory Vesicles - enzymology
Secretory Vesicles - ultrastructure
Synapses - enzymology
Synaptic Vesicles - metabolism
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Summary:Despite a key role for dense core vesicles (DCVs) in neuronal function, there are major gaps in our understanding of DCV biogenesis. A genetic screen for Caenorhabditis elegans mutants with behavioral defects consistent with impaired DCV function yielded five mutations in UNC-108 (Rab2). A genetic analysis showed that unc-108 mutations impair a DCV function unrelated to neuropeptide release that, together with neuropeptide release, fully accounts for the role of DCVs in locomotion. An electron microscopy analysis of DCVs in unc-108 mutants, coupled with quantitative imaging of DCV cargo proteins, revealed that Rab2 acts in cell somas during DCV maturation to prevent the loss of soluble and membrane cargo. In Rab2 null mutants, two thirds of these cargoes move to early endosomes via a PI(3)P-dependent trafficking pathway, whereas aggregated neuropeptides are unaffected. These results reveal how neurons solve a challenging trafficking problem using the most highly conserved animal Rab.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.200902095