CXCR7 Mediates Neural Progenitor Cells Migration to CXCL12 Independent of CXCR4.
CXCR7 Mediates Neural Progenitor Cells Migration to CXCL12 Independent of CXCR4.
复制标题
CXCR7 不依赖于 CXCR4 介导神经祖细胞向 CXCL12 迁移
DOI：
10.1002/stem.2022
复制
发表时间：
2015-08
期刊：
影响因子：
--
通讯作者：
Zheng JC
中科院分区：
文献类型：
--
作者：
Chen Q;Zhang M;Li Y;Xu D;Wang Y;Song A;Zhu B;Huang Y;Zheng JC
神经前体细胞（NPC）迁移是脑发育、成体神经发生和脑损伤后神经再生的重要过程。基质细胞衍生因子-1（SDF-1，CXCL 12）及其传统受体CXCR 4被公认为调节NPC迁移。然而，新发现的CXCL 12受体CXCR 7的发现增加了现有CXCL 12/CXCR 4对的动力学。在transwell趋化性试验中，CXCR 4或CXCR 7的拮抗剂阻断了CXCL 12介导的NPC迁移，表明这两种受体都是CXCL 12作用所必需的。我们从Cxcr 4基因敲除（KO）小鼠中获得NPC培养物，并使用transwell和条纹试验来确定细胞迁移。来自Cxcr 4 KO小鼠的NPC响应于CXCL 12梯度而极化和迁移，表明CXCR 7可以作为独立的迁移受体。此外，移植到成年小鼠纹状体中的Cxcr 4 KO NPC响应于邻近注射CXCL 12而迁移，这一作用被CXCR 7拮抗剂阻断，表明CXCR 7也介导NPC体内迁移。分子机制研究表明，CXCR 7与Rac 1在极化的NPC的前缘CXCR 4的情况下，相互作用。CXCR 7和Rac 1都是细胞外信号调节激酶（ERK）12激活和随后的NPC迁移所必需的，表明CXCR 7可以作为CXCL 12介导的NPC迁移中的功能性受体，而不依赖于CXCR 4。总之，这些结果揭示了CXCR 7在CXCL 12介导的NPC迁移中的重要作用，这对于了解发育期间和成年期的神经发生非常重要。
Neural progenitor cell (NPC) migration is an essential process for brain development, adult neurogenesis, and neuroregeneration after brain injury. Stromal cell-derived factor-1 (SDF-1, CXCL12) and its traditional receptor CXCR4 are well known to regulate NPC migration. However, the discovery of CXCR7, a newly identified CXCL12 receptor, adds to the dynamics of the existing CXCL12/CXCR4 pair. Antagonists for either CXCR4 or CXCR7 blocked CXCL12-mediated NPC migration in a transwell chemotaxis assay, suggesting that both receptors are required for CXCL12 action. We derived NPC cultures from Cxcr4 knockout (KO) mice and used transwell and stripe assays to determine the cell migration. NPCs derived from Cxcr4 KO mice polarized and migrated in response to CXCL12 gradient, suggesting that CXCR7 could serve as an independent migration receptor. Furthermore, Cxcr4 KO NPCs transplanted into the adult mouse striatum migrated in response to the adjacent injection of CXCL12, an effect that was blocked by a CXCR7 antagonist, suggesting that CXCR7 also mediates NPC migration in vivo. Molecular mechanism studies revealed that CXCR7 interact with Rac1 in the leading edge of the polarized NPCs in the absence of CXCR4. Both CXCR7 and Rac1 are required for extracellular signal-regulated kinases (ERK) 1/2 activation and subsequent NPC migration, indicating that CXCR7 could serve as a functional receptor in CXCL12-mediated NPC migration independent of CXCR4. Together these results reveal an essential role of CXCR7 for CXCL12-mediated NPC migration that will be important to understand neurogenesis during development and in adulthood.