The Cell Death Pathway Regulates Synapse Elimination through Cleavage of Gelsolin in Caenorhabditis elegans Neurons

Abstract

Summary Synapse elimination occurs in development, plasticity and disease conditions. Although the importance of synapse elimination has been documented in many studies, the molecular mechanisms underlying this process remain to be understood. Here, using the development of C. elegans RME neurons as a model, we have uncovered the function of the apoptosis pathway in synapse elimination. We find that the conserved apoptotic cell death (CED) pathway and axonal mitochondria are required for elimination of transiently formed clusters of presynaptic components in RME neurons. The function of the CED pathway needs the activation of the actin filament severing protein, GSNL-1. Furthermore, we show that caspase CED-3 cleaves GSNL-1 at a conserved C-terminal region, and that the cleaved active form of GSNL-1 promotes its actin severing ability. Our data suggest that activation of the cell death pathway contributes to selective elimination of synapses through disassembly of actin filament network.

Regulation of neuronal axon specification by glia-neuron gap junctions in C. elegans

“…As shown in Figure 1H, growing animals at the restrictive temperature (11°C) before the L1 stage or after the L4 stage showed the same degree of RME defects as those cultured at the permissive temperature (25°C), but growing larval-stage animals (L1-middle L4) at the restrictive temperature (11°C) was sufficient to cause RME defects to the same extent as those cultured at the restrictive temperature (11°C). These results support the conclusion that unc-1 functions in the larval stages, the same time period of RME D/V neurite development (Meng et al, 2015), to regulate the establishment of RME axon specification.…”

“…To study neural circuit formation in vivo, we used the C. elegans RME circuit as a model (Meng et al, 2015). The circuit contains four GABAergic motor neurons, RMED, RMEV, RMEL, and RMER, that reside at the nerve ring region to control head movement (Song et al, 2010; White et al, 1986).…”

“…In our previous studies, we show that RME neurons form transient synapses at the end of D/V neurites at the L1 stage, and the cell death (CED) pathway can regulate the elimination of those transient synapses through cleavage of a F-actin severing protein GSNL-1/gelsolin (Meng et al, 2015). CED mutants ( egl-1(lf) , ced-9(gf) , ced-3(lf) and ced-4(lf)) or gsnl-1(lf) prevent the elimination of transient synapses in D/V neurites, and as a result SNB-1::GFP puncta are observed at the end of D/V neurites in adult animals.…”

Neural circuit rewiring: insights from DD synapse remodeling

“…33 Four decades after John White's seminal work, we have learned a great deal about DD remodeling, which has provided a rich platform to study the temporal cues 4,6,7,9,10,14,17 as well as the cellular mechanisms that underlie this complete inversion of synaptic connectivity. [22][23][24] Our findings have also revealed a novel role of dynamic MTs in regulating synaptic vesicle transport in the absence of neurite growth or pruning. A recurring theme from these studies is that DD remodeling is guarded by genetic redundancy involving multiple pathways.…”

“…23 Concurrent to new synapse formation to dorsal muscles, existing synapses are eliminated from the ventral neurite of DD neurons, and some synaptic vesicle components appear to be recycled during new synapse formation. 23 Emerging evidence implicates both a cyclin Y homolog CYY-1 23 , and the cell death pathway 24 in DD synapse elimination, but the link between the 2 pathways remains to be addressed.…”