Serping1/C1 Inhibitor Affects Cortical Development in a Cell Autonomous and Non-cell Autonomous Manner.
Serping1/C1 Inhibitor Affects Cortical Development in a Cell Autonomous and Non-cell Autonomous Manner.
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DOI：
10.3389/fncel.2017.00169
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发表时间：
2017
影响因子：
5.3
通讯作者：
Reiner O
中科院分区：
文献类型：
--
作者：
Gorelik A;Sapir T;Woodruff TM;Reiner O
目前关于放射状神经元迁移调控的知识主要集中在细胞内分子上。我们的无偏筛选旨在识别参与这一过程的非细胞自主机制，检测到Serping1或C1抑制剂的差异表达，这是已知的抑制补体级联的启动。补体级联由三条途径组成：经典途径、凝集素途径和替代途径；前两条途径被C1抑制剂抑制，三条途径都在C3水平汇聚。Serping1基因的敲除或敲除影响了小鼠神经干细胞的增殖和受损的神经元迁移。通过宫内电穿孔敲除Serping1，导致电穿孔细胞及其邻近细胞的迁移延迟，表现出非细胞自主效应。细胞的极性也受到了影响。最重要的是，模拟裂解C3的蛋白质组分的表达挽救了Serping1的敲除，表明补体途径的功能。此外，我们认为这种活性主要是通过补体多肽C5a受体介导的。虽然添加选择性C3a受体激动剂的效果甚微，但添加双重C3aR/C5a受体激动剂显著挽救了Serping1基因敲除介导的神经元迁移缺陷。我们的发现表明，调节发育中大脑中的Serping1水平可能会以一种复杂的方式影响补体途径。总而言之，我们的发现表明，在大脑发育过程中，补体途径具有非常规的活性。
Current knowledge regarding regulation of radial neuronal migration is mainly focused on intracellular molecules. Our unbiased screen aimed at identification of non-cell autonomous mechanisms involved in this process detected differential expression of Serping1 or C1 inhibitor, which is known to inhibit the initiation of the complement cascade. The complement cascade is composed of three pathways; the classical, lectin, and the alternative pathway; the first two are inhibited by C1 inhibitor, and all three converge at the level of C3. Knockdown or knockout of Serping1 affected neuronal stem cell proliferation and impaired neuronal migration in mice. Knockdown of Serping1 by in utero electroporation resulted in a migration delay of the electroporated cells as well as their neighboring cells demonstrating a non-cell autonomous effect. Cellular polarity was also affected. Most importantly, expression of protein components mimicking cleaved C3 rescued the knockdown of Serping1, indicating complement pathway functionality. Furthermore, we propose that this activity is mediated mainly via the complement peptide C5a receptors. Whereas addition of a selective C3a receptor agonist was minimally effective, the addition of a dual C3aR/C5a receptor agonist significantly rescued Serping1 knockdown-mediated neuronal migration defects. Our findings suggest that modulating Serping1 levels in the developing brain may affect the complement pathway in a complex way. Collectively, our findings demonstrate an unorthodox activity for the complement pathway during brain development.