Sorkaç Altar, DiIorio Michael A, O'Hern Patrick J, Baskoylu Saba N, Graham Hannah K, Hart Anne C
Department of Neuroscience, Brown University, Providence, Rhode Island, 02912.
Department of Neuroscience, Brown University, Providence, Rhode Island, 02912
G3 (Bethesda). 2018 Jul 31;8(8):2825-2832. doi: 10.1534/g3.118.200202.
The role of Notch signaling in cell-fate decisions has been studied extensively; however, this pathway is also active in adult tissues, including the nervous system. Notch signaling modulates a wide range of behaviors and processes of the nervous system in the nematode , but there is no evidence for Notch signaling directly altering synaptic strength. Here, we demonstrate Notch-mediated regulation of synaptic activity at the neuromuscular junction (NMJ). For this, we used aldicarb, an inhibitor of the enzyme acetylcholinesterase, and assessed paralysis rates of animals with altered Notch signaling. Notch receptors LIN-12 and GLP-1 are required for normal NMJ function; they regulate NMJ activity in an opposing fashion. Complete loss of LIN-12 skews the excitation/inhibition balance at the NMJ toward increased activity, whereas partial loss of GLP-1 has the opposite effect. Specific Notch ligands and co-ligands are also required for proper NMJ function. The role of LIN-12 is independent of cell-fate decisions; manipulation of LIN-12 signaling through RNAi knockdown or overexpression of the co-ligand OSM-11 after development alters NMJ activity. We demonstrate that LIN-12 modulates GABA signaling in this paradigm, as loss of GABA signaling suppresses LIN-12 gain-of-function defects. Further analysis, and , suggests that LIN-12 may modulate transcription of the GABA receptor GBB-2 Our findings confirm a non-developmental role for the LIN-12/Notch receptor in regulating synaptic signaling and identify the GABA receptor GBB-2 as a potential Notch transcriptional target in the nervous system.
Notch信号通路在细胞命运决定中的作用已得到广泛研究；然而，该通路在包括神经系统在内的成体组织中也具有活性。Notch信号通路调节线虫神经系统的多种行为和过程，但尚无证据表明Notch信号通路直接改变突触强度。在此，我们证明了Notch在神经肌肉接头（NMJ）处对突触活性的调节作用。为此，我们使用了涕灭威，一种乙酰胆碱酯酶抑制剂，并评估了Notch信号通路改变的动物的麻痹率。Notch受体LIN-12和GLP-1是正常NMJ功能所必需的；它们以相反的方式调节NMJ活性。LIN-12的完全缺失会使NMJ处的兴奋/抑制平衡向活性增加倾斜，而GLP-1的部分缺失则具有相反的效果。特定的Notch配体和共配体也是正常NMJ功能所必需的。LIN-12的作用独立于细胞命运决定；发育后通过RNA干扰敲低或共配体OSM-11的过表达来操纵LIN-12信号通路会改变NMJ活性。我们证明在这种模式下LIN-12调节GABA信号通路，因为GABA信号通路的缺失会抑制LIN-12功能获得性缺陷。进一步的分析表明，LIN-12可能调节GABA受体GBB-2的转录。我们的研究结果证实了LIN-12/Notch受体在调节突触信号传导中的非发育作用，并确定GABA受体GBB-2是神经系统中潜在的Notch转录靶点。
