Abstract
Synapses are actively dismantled to mediate circuit refinement, but the developmental pathways that regulate synaptic disassembly are largely unknown. We have previously shown that the epithelial sodium channel ENaC/UNC-8 triggers an activity-dependent mechanism that drives the removal of presynaptic proteins liprin-α/SYD-2, Synaptobrevin/SNB-1, RAB-3, and Endophilin/UNC-57 in remodeling GABAergic neurons in Caenorhabditis elegans (Miller-Fleming et al., 2016). Here, we report that the conserved transcription factor Iroquois/IRX-1 regulates UNC-8 expression as well as an additional pathway, independent of UNC-8, that functions in parallel to dismantle functional presynaptic terminals. We show that the additional IRX-1-regulated pathway is selectively required for the removal of the presynaptic proteins, Munc13/UNC-13 and ELKS, which normally mediate synaptic vesicle (SV) fusion and neurotransmitter release. Our findings are notable because they highlight the key role of transcriptional regulation in synapse elimination during development and reveal parallel-acting pathways that coordinate synaptic disassembly by removing specific active zone proteins.SIGNIFICANCE STATEMENT Synaptic pruning is a conserved feature of developing neural circuits but the mechanisms that dismantle the presynaptic apparatus are largely unknown. We have determined that synaptic disassembly is orchestrated by parallel-acting mechanisms that target distinct components of the active zone. Thus, our finding suggests that synaptic disassembly is not accomplished by en masse destruction but depends on mechanisms that dismantle the structure in an organized process.
Highlights
Jin 1998; White, Albertson, and Anness 1978)
Unlike other presynaptic markers, Rim1/UNC-10::GFP does not remodel in unc-55 mutants and is retained on the ventral side (Figure 3G). These results suggest that dual localization of both RAB-3 and Rim1/UNC-10 in ventral GABAergic synapses of unc-55; unc-8 and unc-55; irx-1(csRNAi) mutants could account for our EM observation of numerous docked vesicles (Figure 5B-C)
Our results support the idea that Iroquois/IRX-1 removes ELKS-1 from ventral synapses of remodeling GABAergic motor neurons in a genetic pathway that is independent of UNC-8 (Figure 8L-M). 575 To summarize, our results show that IRX-1 drives the removal of multiple components of the 576 presynaptic apparatus in remodeling GABAergic neurons including Synaptobrevin/SNB-1, RAB577 3, liprin-D/SYD-2, Endophilin/UNC-57, UNC-13L and ELKS-1 (Figures 3, 4, 7 and 8)
Summary
11 26 27 Number of words for abstract: 147 28 29 Number of words for introduction: 655 30 31 Number of words for discussion: 1149 32. The COUP-TF transcription factor, UNC-55, is selectively expressed in VD neurons to prevent synaptic remodeling (Shan et al 2005; Zhou and Walthall 1998); in unc-55 mutants, VD neurons initially synapse with ventral muscles but mimic the native DD remodeling program by relocating presynaptic domains to the dorsal nerve cord (Figure 1C) (Petersen et al 2011; Thompson-Peer et al 2012). Proteins involved in synaptic vesicle priming, UNC-13/Munc-13 and ELKS, are not disassembled by UNC-8 but are removed by a separate pathway regulated by IRX-1/Iroquois Together, these findings show that remodeling of GABAergic synapses depends on the combined effects of neural activity (UNC-8). Our work shows that synaptic disassembly can be orchestrated by parallel-acting mechanisms that selectively target molecularly distinct components of the presynaptic apparatus for removal
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
