The β-chemokines CCL2 and CCL7 are two novel differentiation factors for midbrain dopaminergic precursors and neurons
The β-chemokines CCL2 and CCL7 are two novel differentiation factors for midbrain dopaminergic precursors and neurons
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DOI：
10.1016/j.yexcr.2008.02.019
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发表时间：
2008-06-10
影响因子：
3.7
通讯作者：
Arenas, Ernest
中科院分区：
文献类型：
--
作者：
Edman, Linda C.;Mira, Helena;Arenas, Ernest
β-趋化因子是调节成人脑中多种功能如神经免疫反应和神经传递的分泌因子，但它们在发育中的脑中的功能在很大程度上是未知的。我们最近发现孤儿核受体Nurr 1上调神经干细胞中的CCL 2和CCL 7，这表明β-趋化因子在中脑发育中可能具有功能。在这里，我们报告，两个β-趋化因子，CCL 2和CCL 7，和他们的两个受体，CCR 1和CCR 2，在腹侧中脑（VM）的表达和发育调节。此外，我们发现CCL 7的表达在Nurr 1基因敲除小鼠中下调，将CCL 7与多巴胺（DA）神经元发育联系起来。当检查CCL 2和CCL 7的功能时，我们发现它们选择性地增强Nurr 1+前体向DA神经元的分化，但在原代前体培养物中不增强它们的存活或祖细胞增殖。此外，CCL 2和CCL 7促进中脑DA神经元培养中的轴突发生。因此，我们的研究结果首次显示了β-趋化因子在发育中的大脑中的功能，并确定β-趋化因子作为中脑DA神经元的新型促分化因子。这些数据还表明，β-趋化因子可能成为有用的工具，以提高分化的DA细胞制剂的细胞替代疗法和药物发现在帕金森氏病（PD）。(c)2008年爱思唯尔公司All rights reserved.
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). (c) 2008 Elsevier Inc. All rights reserved.