N-glycosylation requirements in neuromuscular synaptogenesis
N-glycosylation requirements in neuromuscular synaptogenesis
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DOI：
10.1242/dev.099192
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发表时间：
2013-12
期刊：
影响因子：
4.6
通讯作者：
W. Parkinson;M. L. Dear;E. Rushton;K. Broadie
中科院分区：
文献类型：
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作者：
W. Parkinson;M. L. Dear;E. Rushton;K. Broadie
神经发育需要细胞间信号传导的 N-糖基化调节，但突触发生的要求尚未得到充分测试。所有复杂和混合的 N-糖基化都需要 MGAT1 (UDP-GlcNAc:α-3-D-甘露糖苷-β1,2-N-乙酰氨基葡萄糖转移酶 I) 功能，而 Mgat1 无效是最受损的 N-糖基化条件，可以存活足够长的时间以进行突触发生研究。在果蝇神经肌肉接头 (NMJ) 处，Mgat1 突变体表现出细胞外突触基质中凝集素定义的碳水化合物的选择性丢失，并伴随分泌的内源性凝集素 (MTG) 凝集素（一种关键的突触发生调节剂）的积累。空 Mgat1 突变体表现出强烈过度精细的突触结构发育，与形态突触发生中复杂/混合 N-聚糖的抑制作用一致，并增强功能性突触分化，与突触发生 MTG 功能一致。令人惊讶的是，突触分子组成发生了选择性改变，突触前活性区 Bruchpilot (BRP) 和突触后谷氨酸受体亚型 B (GLURIIB) 减少，但其他突触成分没有可检测到的变化。突触发生是由穿过富含聚糖的突触基质的双向跨突触信号驱动的，Mgat1 突变会破坏顺行和逆行信号，这与 MTG 对跨突触信号的调节一致。在细胞间信号传导的下游，突触前和突触后支架被募集来驱动突触发生，Mgat1 突变体表现出经典的 Discs Large 1 (DLG1) 和新定义的 Lethal (2) 巨型幼虫 [L(2)GL] 支架的丢失。我们得出的结论是，MGAT1 依赖性 N-糖基化塑造了突触基质碳水化合物环境和内源性凝集素在该结构域内的定位，以调节跨突触信号配体的保留，从而在突触发生过程中驱动突触支架募集。
Neural development requires N-glycosylation regulation of intercellular signaling, but the requirements in synaptogenesis have not been well tested. All complex and hybrid N-glycosylation requires MGAT1 (UDP-GlcNAc:α-3-D-mannoside-β1,2-N-acetylglucosaminyl-transferase I) function, and Mgat1 nulls are the most compromised N-glycosylation condition that survive long enough to permit synaptogenesis studies. At the Drosophila neuromuscular junction (NMJ), Mgat1 mutants display selective loss of lectin-defined carbohydrates in the extracellular synaptomatrix, and an accompanying accumulation of the secreted endogenous Mind the gap (MTG) lectin, a key synaptogenesis regulator. Null Mgat1 mutants exhibit strongly overelaborated synaptic structural development, consistent with inhibitory roles for complex/hybrid N-glycans in morphological synaptogenesis, and strengthened functional synapse differentiation, consistent with synaptogenic MTG functions. Synapse molecular composition is surprisingly selectively altered, with decreases in presynaptic active zone Bruchpilot (BRP) and postsynaptic Glutamate receptor subtype B (GLURIIB), but no detectable change in a wide range of other synaptic components. Synaptogenesis is driven by bidirectional trans-synaptic signals that traverse the glycan-rich synaptomatrix, and Mgat1 mutation disrupts both anterograde and retrograde signals, consistent with MTG regulation of trans-synaptic signaling. Downstream of intercellular signaling, pre- and postsynaptic scaffolds are recruited to drive synaptogenesis, and Mgat1 mutants exhibit loss of both classic Discs large 1 (DLG1) and newly defined Lethal (2) giant larvae [L(2)GL] scaffolds. We conclude that MGAT1-dependent N-glycosylation shapes the synaptomatrix carbohydrate environment and endogenous lectin localization within this domain, to modulate retention of trans-synaptic signaling ligands driving synaptic scaffold recruitment during synaptogenesis.