Dr. Stefan Eimer
European Neuroscience Institute (ENI), Goettingen and DFG Reseach Center for Molecular Physiology of the Brain (CMPB), Goettingen

"Regulation of Dense Core Vesicle biogenesis and function by Rab GTPases in C. elegans"

Small GTPases of the Rab family are the main regulators of intracellular vesicular trafficking. To find new Rab proteins that regulate synaptic transmission, we have undertaken a systematic approach to functionally characterize all 26 Rab GTPases in C. elegans. RAB-2 is the most highly conserved Rab in animals and is highly expressed in the nervous system, yet its function in neurons is unknown. In C. elegans, unc-108/rab-2 loss- and gain-of-function mutants have been isolated based on their slow movement suggesting defects in neurotransmission. We show that the locomotion defects of rab-2 mutant animals are not caused by defects in SV release, but by defects in dense core vesicle (DCV) signaling. We show that while their number and distribution of DCVs is not affected, DCVs in rab-2 mutants are often enlarged and heterogeneous in size. This implicates RAB-2 in the biogenesis of DCVs at the Golgi complex. We demonstrate that in rab-2 mutants DCV cargo inappropriately enters late endosomal compartments during DCV maturation. Finally we show that RIC-19, the C. elegans ortholog of the human diabetes autoantigen ICA69, is also involved in DCV biogenesis and recruited to Golgi membranes by activated RAB-2. Thus, we propose that RAB-2 and its effector RIC-19 are required for neuronal DCV maturation in C. elegans.