The endogenous neuronal complement inhibitor SRPX2 protects against complement-mediated synapse elimination during development
The endogenous neuronal complement inhibitor SRPX2 protects against complement-mediated synapse elimination during development
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DOI：
10.1038/s41593-020-0672-0
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发表时间：
2020-07-13
影响因子：
25
通讯作者：
Sia, Gek-Ming
中科院分区：
文献类型：
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作者：
Cong, Qifei;Soteros, Breeanne M.;Sia, Gek-Ming
补体介导的突触消除已经成为脑发育和神经系统疾病中的重要过程，但神经元是否表达补体抑制剂以保护突触免受补体介导的突触消除仍然未知。在这里，我们表明，寿司结构域蛋白SRPX 2是一种神经表达的补体抑制剂，调节补体依赖性突触消除。SRPX 2直接与C1 q结合并阻断其活性，SRPX 2（-/Y）小鼠显示C3沉积和小胶质细胞突触吞噬增加。它们还显示突触数量的短暂减少和外侧膝状体中视网膜膝状体轴突分离的增加。在躯体感觉皮层，SRPX 2（-/Y）小鼠表现出丘脑皮层突触数量减少和脊髓修剪增加; C3（-/-）; SRPX 2（-/Y）双敲除小鼠表现出与C3（-/-）小鼠相关的表型，而非SRPX 2（-/Y）小鼠，这表明C3是SRPX 2消除突触的作用所必需的。总之，这些结果表明，SRPX 2保护突触免受补体介导的消除在丘脑和皮质。补体-小胶质细胞途径是一个关键介质的突触消除在发展和疾病。Cong等人表明，神经元内源性表达补体抑制剂SRPX 2，其调节发育中的突触消除。
Complement-mediated synapse elimination has emerged as an important process in both brain development and neurological diseases, but whether neurons express complement inhibitors that protect synapses against complement-mediated synapse elimination remains unknown. Here, we show that the sushi domain protein SRPX2 is a neuronally expressed complement inhibitor that regulates complement-dependent synapse elimination. SRPX2 directly binds to C1q and blocks its activity, andSRPX2(-/Y)mice show increased C3 deposition and microglial synapse engulfment. They also show a transient decrease in synapse numbers and increase in retinogeniculate axon segregation in the lateral geniculate nucleus. In the somatosensory cortex,SRPX2(-/Y)mice show decreased thalamocortical synapse numbers and increased spine pruning.C3(-/-);SRPX2(-/Y)double-knockout mice exhibit phenotypes associated withC3(-/-)mice rather thanSRPX2(-/Y)mice, which indicates that C3 is necessary for the effect of SRPX2 on synapse elimination. Together, these results show that SRPX2 protects synapses against complement-mediated elimination in both the thalamus and the cortex.The complement-microglia pathway is a key mediator of synapse elimination in development and disease. Cong et al. show that neurons endogenously express a complement inhibitor, SRPX2, that regulates synapse elimination in development.