Edman Linda C, Mira Helena, Arenas Ernest
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Scheeles väg 1, 17177 Stockholm, Sweden.
Exp Cell Res. 2008 Jun 10;314(10):2123-30. doi: 10.1016/j.yexcr.2008.02.019. Epub 2008 Mar 8.
beta-chemokines are secreted factors that regulate diverse functions in the adult brain, such as neuro-immune responses and neurotransmission, but their function in the developing brain is largely unknown. We recently found that the orphan nuclear receptor, Nurr1, up regulates CCL2 and CCL7 in neural stem cells, suggesting a possible function of beta-chemokines in midbrain development. Here we report that two beta-chemokines, CCL2 and CCL7, and two of their receptors, CCR1 and CCR2, are expressed and developmentally regulated in the ventral midbrain (VM). Moreover, we found that the expression of CCL7 was down regulated in the Nurr1 knockout mice, linking CCL7 to dopamine (DA) neuron development. When the function of CCL2 and CCL7 was examined, we found that they selectively enhanced the differentiation of Nurr1+ precursors into DA neurons, but not their survival or progenitor proliferation in primary precursor cultures. Moreover, both CCL2 and CCL7 promoted neuritogenesis in midbrain DA neuron cultures. Thus, our results show for the first time a function of beta-chemokines in the developing brain and identify beta-chemokines as novel class of pro-differentiation factors for midbrain DA neurons. These data also suggest that beta-chemokines may become useful tools to enhance the differentiation of DA cell preparations for cell replacement therapy and drug discovery in Parkinson's disease (PD).
β-趋化因子是分泌因子，可调节成人大脑中的多种功能，如神经免疫反应和神经传递，但其在发育中大脑的功能在很大程度上尚不清楚。我们最近发现，孤儿核受体Nurr1可上调神经干细胞中的CCL2和CCL7，提示β-趋化因子在中脑发育中可能具有某种功能。在此我们报告，两种β-趋化因子CCL2和CCL7及其两种受体CCR1和CCR2在腹侧中脑（VM）中表达且受发育调控。此外，我们发现CCL7在Nurr1基因敲除小鼠中的表达下调，将CCL7与多巴胺（DA）神经元发育联系起来。当检测CCL2和CCL7的功能时，我们发现它们可选择性增强Nurr1+前体细胞向DA神经元的分化，但在原代前体细胞培养中对其存活或祖细胞增殖无影响。此外，CCL2和CCL7均可促进中脑DA神经元培养中的神经突生长。因此，我们的结果首次显示了β-趋化因子在发育中大脑的功能，并将β-趋化因子确定为中脑DA神经元的一类新型促分化因子。这些数据还表明，β-趋化因子可能成为增强DA细胞制剂分化的有用工具，用于帕金森病（PD）的细胞替代治疗和药物发现。
