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C. elegans RPM-1 regulates axon termination and synaptogenesis through the Rab GEF GLO-4 and the Rab GTPase GLO-1.
C. elegans RPM-1 (for Regulator of Presynaptic Morphology) is a member of a conserved protein family that includes Drosophila Highwire and mammalian Pam and Phr1. These are large proteins recently shown to regulate synaptogenesis through E3 ubiquitin ligase activities. Here, we report the identification of an RCC1-like guanine nucleotide exchange factor, GLO-4, from mass spectrometry analysis of RPM-1-associated proteins. GLO-4 colocalizes with RPM-1 at presynaptic terminals. Loss of function in glo-4 or in its target Rab GTPase, glo-1, causes neuronal defects resembling those in rpm-1 mutants. We show that the glo pathway functions downstream of rpm-1 and acts in parallel to fsn-1, a partner of RPM-1 E3 ligase function. We find that late endosomes are specifically disorganized at the presynaptic terminals of glo-4 mutants. Our data suggest that RPM-1 positively regulates a Rab GTPase pathway to promote vesicular trafficking via late endosomes.
Animals, Animals, Genetically Modified, Caenorhabditis elegans, Caenorhabditis elegans Proteins/analysis, Caenorhabditis elegans Proteins/metabolism, Green Fluorescent Proteins/metabolism, Guanine Nucleotide Exchange Factors/analysis, Guanine Nucleotide Exchange Factors/metabolism, Immunoprecipitation/methods, Mass Spectrometry/methods, Mutation/physiology, Neurons/classification, Neurons/cytology, Presynaptic Terminals/physiology, Protein Transport/physiology, Subcellular Fractions/metabolism, Synapses/physiology, rab GTP-Binding Proteins/metabolism
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