Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles väg 1, 17177 Stockholm, Sweden.
Development. 2013 Nov;140(22):4554-64. doi: 10.1242/dev.098145. Epub 2013 Oct 23.
CXCL12/CXCR4 signaling has been reported to regulate three essential processes for the establishment of neural networks in different neuronal systems: neuronal migration, cell positioning and axon wiring. However, it is not known whether it regulates the development of A9-A10 tyrosine hydroxylase positive (TH(+)) midbrain dopaminergic (mDA) neurons. We report here that Cxcl12 is expressed in the meninges surrounding the ventral midbrain (VM), whereas CXCR4 is present in NURR1(+) mDA precursors and mDA neurons from E10.5 to E14.5. CXCR4 is activated in NURR1(+) cells as they migrate towards the meninges. Accordingly, VM meninges and CXCL12 promoted migration and neuritogenesis of TH(+) cells in VM explants in a CXCR4-dependent manner. Moreover, in vivo electroporation of Cxcl12 at E12.5 in the basal plate resulted in lateral migration, whereas expression in the midline resulted in retention of TH(+) cells in the IZ close to the midline. Analysis of Cxcr4(-/-) mice revealed the presence of VM TH(+) cells with disoriented processes in the intermediate zone (IZ) at E11.5 and marginal zone (MZ) at E14. Consistently, pharmacological blockade of CXCR4 or genetic deletion of Cxcr4 resulted in an accumulation of TH(+) cells in the lateral aspect of the IZ at E14, indicating that CXCR4 is required for the radial migration of mDA neurons in vivo. Altogether, our findings demonstrate that CXCL12/CXCR4 regulates the migration and orientation of processes in A9-A10 mDA neurons.
CXCL12/CXCR4 信号已被报道调节不同神经元系统中神经网络建立的三个基本过程：神经元迁移、细胞定位和轴突布线。然而，尚不清楚它是否调节 A9-A10 酪氨酸羟化酶阳性（TH(+)）中脑多巴胺能（mDA）神经元的发育。我们在这里报告 Cxcl12 在腹侧中脑（VM）周围脑膜中表达，而 CXCR4 存在于 E10.5 至 E14.5 的 NURR1(+) mDA 前体和 mDA 神经元中。CXCR4 在向脑膜迁移的 NURR1(+)细胞中被激活。因此，VM 脑膜和 CXCL12 以 CXCR4 依赖的方式促进 VM 外植体中 TH(+)细胞的迁移和神经突发生。此外，在 E12.5 在基板中电穿孔 Cxcl12 导致侧向迁移，而在中线表达导致 TH(+)细胞保留在靠近中线的 IZ 中。对 Cxcr4(-/-)小鼠的分析表明，在 E11.5 时 VM TH(+)细胞的轴突在中间区（IZ）中定向紊乱，在 E14.5 时在边缘区（MZ）中定向紊乱。一致地，CXCR4 的药理学阻断或 Cxcr4 的基因缺失导致 E14 时 TH(+)细胞在 IZ 的外侧堆积，表明 CXCR4 是 mDA 神经元在体内的放射状迁移所必需的。总之，我们的发现表明 CXCL12/CXCR4 调节 A9-A10 mDA 神经元的迁移和突起的定向。
