Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany.
Development. 2014 May;141(9):1857-63. doi: 10.1242/dev.104224. Epub 2014 Apr 9.
The CXCL12/CXCR4 signaling pathway is involved in the development of numerous neuronal and non-neuronal structures. Recent work established that the atypical second CXCL12 receptor, CXCR7, is essential for the proper migration of interneuron precursors in the developing cerebral cortex. Two CXCR7-mediated functions were proposed in this process: direct modulation of β-arrestin-mediated signaling cascades and CXCL12 scavenging to regulate local chemokine availability and ensure responsiveness of the CXCL12/CXCR4 pathway in interneurons. Neither of these functions has been proven in the embryonic brain. Here, we demonstrate that migrating interneurons efficiently sequester CXCL12 through CXCR7. CXCR7 ablation causes excessive phosphorylation and downregulation of CXCR4 throughout the cortex in mice expressing CXCL12, but not in CXCL12-deficient animals. Cxcl12(-/-) mice lack activated CXCR4 in embryonic brain lysates and display a similar interneuron positioning defect as Cxcr4(-/-), Cxcr7(-/-) and Cxcl12(-/-);Cxcr7(-/-) animals. Thus, CXCL12 is the only CXCR4-activating ligand in the embryonic brain and deletion of one of the CXCL12 receptors is sufficient to generate a migration phenotype that corresponds to the CXCL12-deficient pathway. Our findings imply that interfering with the CXCL12-scavenging activity of CXCR7 causes loss of CXCR4 function as a consequence of excessive CXCL12-mediated CXCR4 activation and degradation.
CXCL12/CXCR4 信号通路参与许多神经元和非神经元结构的发育。最近的研究工作表明，非典型的第二种 CXCL12 受体 CXCR7 对于大脑皮层发育过程中中间神经元前体的正确迁移至关重要。在这个过程中提出了 CXCR7 介导的两种功能：直接调节β-arrestin 介导的信号级联反应和 CXCL12 的清除，以调节局部趋化因子的可用性，并确保 CXCL12/CXCR4 途径在中间神经元中的反应性。这两种功能都尚未在胚胎大脑中得到证明。在这里，我们证明迁移的中间神经元通过 CXCR7 有效地隔离 CXCL12。在表达 CXCL12 的小鼠中，CXCR7 缺失会导致整个皮层中 CXCR4 的过度磷酸化和下调，但在 CXCL12 缺陷型动物中则不会。Cxcl12(-/-) 小鼠在胚胎脑裂解物中缺乏激活的 CXCR4，并显示出与 Cxcr4(-/-)、Cxcr7(-/-) 和 Cxcl12(-/-);Cxcr7(-/-) 动物相似的中间神经元定位缺陷。因此，CXCL12 是胚胎脑中唯一激活 CXCR4 的配体，并且删除一种 CXCL12 受体就足以产生与 CXCL12 缺陷途径相对应的迁移表型。我们的研究结果表明，干扰 CXCR7 的 CXCL12 清除活性会导致 CXCR4 功能丧失，这是由于 CXCL12 介导的 CXCR4 过度激活和降解所致。
