Academic journal article Genetics

Sentryn and SAD Kinase Link the Guided Transport and Capture of Dense Core Vesicles in Caenorhabditis Elegans

Academic journal article Genetics

Sentryn and SAD Kinase Link the Guided Transport and Capture of Dense Core Vesicles in Caenorhabditis Elegans

Article excerpt

NEURONS are perhaps the most complex of all cells. Their complexity arises from the need to send and receive signals from long processes that extend from the cell body. These processes include one or more dendrites, which receive signals, and a single axon. Part of the axon is specialized to form synapses. This part, the synaptic region,transmits signalstoother neurons or muscle cells through the regulated fusion of signaling vesicles with the plasma membrane. Here, we report the discovery of two proteins that have important roles in guiding the motorized transport of one kind of signaling vesicle to the synaptic region and then ensuring that the vesicles halt their transport and become captured in the synaptic region.

Two types of signaling vesicles are found in the synaptic region: synaptic vesicles (SVs) and dense core vesicles (DCVs) (Richmond and Broadie 2002; Sudhof 2004). SVs cluster around a small site known as the active zone (Sudhof 2012), from which they focally release small molecule neurotransmitters in response to electrical signals in the axon. Neurotransmitter release activates postsynaptic receptors that align with the presynaptic active zones. Neuropeptide containing DCVs are often present in lower numbers in the synaptic region, with one study finding ~7% as many DCVs as SVs at worm motor neuron synapses (Sossin and Scheller 1991; Levitan 2008; Hoover etai. 2014). DCV-mediated neuropeptide signaling is important because it can influence and coordinate the activities of neuronal circuits (Liu et ai. 2007; Hu et ai. 2011; Bhattacharya et ai. 2014; Bhattacharya and Francis 2015; Choi et ai. 2015; Chen et ai. 2016; Lim et ai. 2016; Banerjee et ai. 2017) or generally modulate the responsiveness of the presynaptic and postsynaptic cells (Kupfermann 1991; Hu etai. 2015).

DCVs are enriched at synapses relative to the short interaxonal regions between synapses (Wong et al. 2012; Hoover et al. 2014). However, within synapses, the DCV distribution appears random or near-random, not clustered around active zones like SVs. Furthermore, docked DCVs are largely excluded from the active zone, where SVs dock and fuse (Weimer et al 2006; Hammarlund et al. 2008; Hoover et al. 2014). If docked DCVs represent the only fusion locations, the apparent distributed signaling of DCVs within synapses contrasts sharply with the highly focal fusion of SVs at active zones.

The long distance axonal transport of SVs and DCVs requires a sophisticated cargo transport system. This system uses a network of microtubule tracks and motors that exhibit intrinsic directionality. The microtubules have a plus and a minus end, and there are dedicated plus- and minus-end directed motors. The microtubules in axons are almost uniformly oriented, with their plus-ends pointing outward into the axon (Burton and Paige 1981; Heidemann et al. 1981; Baas and Lin 2011). Both SVs and DCVs use the same motors. The plus-end directed (forward) motor KIF1A moves SVs and DCVs from the cell soma to the synaptic region (Hall and Hedgecock 1991; Pack-Chung et al. 2007; Edwards et al. 2015b), while the minus-end directed (reverse) motor dynein moves them in the opposite direction (Ou et al. 2010; Goodwin et al. 2012; Wong et al. 2012; Cavolo et al. 2015; Edwards et al. 2015b). A recent study in flies found that conventional Kinesin also contributes to the guided forward transport of DCVs (Bhattacharya et al. 2014). During transport from the soma to the synaptic region, both the forward and reverse motors act on the same vesicles, causing them to reverse direction multiple times en route to the synaptic region (Edwards etal. 2015b). Although the significance of this bidirectional transport is unknown, its existence necessitates a mechanism for ensuring the ultimate forward progress of vesicles. In other words, the forward motor(s) must outcompete dynein to ensure that optimal levels of SVs and DCVs accumulate in the synaptic region. We refer to this as "guided" axonal transport, or, simply, guided transport. …

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