Academic journal article Genetics

Sentryn Acts with a Subset of Active Zone Proteins to Optimize the Localization of Synaptic Vesicles in Caenorhabditis Elegans

Academic journal article Genetics

Sentryn Acts with a Subset of Active Zone Proteins to Optimize the Localization of Synaptic Vesicles in Caenorhabditis Elegans

Article excerpt

NEURONS are distinguished from other cells by their complexity. Part of this complexity arises from the need to transport signaling vesicles known as synaptic vesicles (SVs) long distances through axons. Furthermore, after transport, neurons must ensure that SVs become captured in clusters in a specialized synaptic region, where synapses form. The synaptic region can be at a nonterminal or a terminal location in the axon, or it can be distributed throughout the axon as part a single process or branched axon processes (Nicholls 2012; Kandel 2013). The captured SVs cluster around small structures known as active zones-the sites where SVs ultimately fuse and release their neurotransmitter cargo (Sudhof 2012). Here, we identify what appears to be a new active zone-enriched protein named Sentryn. Our data suggest that Sentryn is a missing link in a sophisticated system that ensures the stable accumulation of SVs at synapses.

The cargo transport system of neurons 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 nearly uniformly oriented with their plus-ends pointing out (Burton and Paige 1981; Heidemann et al. 1981; Baas and Lin 2011). The plus-end directed (forward) motor KIF1A moves SVs from the cell soma to the synaptic region (Hall and Hedgecock 1991). The minus-end directed (reverse) motor dynein moves them in the opposite direction (Ou et al. 2010; Edwards et al. 2015b). During transport from the soma to the synaptic region, both the forward and reverse motors act on the same SVs, causing them to reverse direction multiple times en route (Wu et al. 2013; Edwards et al. 2015b). Although the significance of this bidirectional transport is unknown, its existence means that neurons must have a mechanism to ensure that KIF1A ultimately dominates, thus allowing optimal levels of SVs to reach the synaptic region. We refer to the process that ensures the dominance of forward transport as "guided transport." Adding complexity, neurons must also have a mechanism to inhibit, block, or equalize the actions of both motors after guided axonal transport to enable SVs to become captured in the synaptic region. In other words, SVs must be protected from counter-productive motor activity both during and after transport.

The core synapse stability (CSS) system contributes to both the guided SV transport and the capture of SVs in the synaptic region. The CSS system is a group of proteins with shared functions in inhibiting the removal of cargos from axons (Edwards et al. 2015a; Miller 2017). The system includes at least three active zone-enriched proteins, SYD-2 (Liprin-a), SAD kinase, and SYD-1. Despite being enriched at active zones, CSS system proteins also affect transport at sites far removed from active zones, since they guide the outward transport of SVs (Miller et al. 2005; Wagner et al. 2009; Zheng et al. 2014; Edwards et al. 2015b). However, the same three proteins also have a post-transport function in the synaptic region near active zones. The synaptic region functions of SYD-2 (Liprin-a), SAD kinase, and SYD-1 were first discovered in Caenorhabditis elegans, when mutant analyses revealed defects in SV cluster formation and synapse assembly (Zhen and Jin 1999; Crump et al. 2001; Hallam et al. 2002; Dai et al. 2006; Patel et al. 2006). Later studies suggested that the role of these proteins in synapse assembly involved capturing SVs to clusters (Stigloher et al. 2011; Kittelmann et al. 2013; Wu et al. 2013; Edwards et al 2015b). SYD-2 and SYD-1 also contribute to the structure of active zones, but are not required for active zone formation (Zhen and Jin 1999; Owald et al. 2010; Kittelmann et al. 2013).

The finding that CSS system proteins act together in the same neurons to regulate both the guided transport and capture of SVs suggests that these two processes may be coordinated or linked in some way, possibly through the regulation of motorized transport by a common set of proteins. …

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