Miller-Fleming Tyne W, Cuentas-Condori Andrea, Manning Laura, Palumbos Sierra, Richmond Janet E, Miller David M
Neuroscience Program, Vanderbilt University, Nashville, Tennessee 37212.
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee 37212.
J Neurosci. 2021 Jul 7;41(27):5849-5866. doi: 10.1523/JNEUROSCI.0893-20.2021.
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 (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. 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.
突触会被主动拆解以介导神经回路的精细化，但调节突触拆解的发育途径在很大程度上尚不清楚。我们之前已经表明，上皮钠通道ENaC/UNC-8触发了一种活动依赖性机制，该机制驱动在重塑γ-氨基丁酸能神经元时去除突触前蛋白脂锚蛋白-α/SYD-2、突触小泡蛋白/SNB-1、RAB-3和内吞蛋白/UNC-57（米勒-弗莱明等人，2016年）。在这里，我们报告保守的转录因子Iroquois/IRX-1调节UNC-8的表达以及另一条独立于UNC-8的途径，该途径与拆解功能性突触前终末的途径并行发挥作用。我们表明，额外受IRX-1调节的途径对于去除通常介导突触小泡（SV）融合和神经递质释放的突触前蛋白Munc13/UNC-13和ELKS是选择性必需的。我们的发现值得注意，因为它们突出了转录调节在发育过程中突触消除中的关键作用，并揭示了通过去除特定活性区蛋白来协调突触拆解的并行作用途径。突触修剪是发育中的神经回路的一个保守特征，但拆解突触前装置的机制在很大程度上尚不清楚。我们已经确定，突触拆解是由针对活性区不同成分的并行作用机制精心安排的。因此，我们的发现表明，突触拆解不是通过大规模破坏来完成的，而是依赖于在一个有组织的过程中拆解结构的机制。
