Proinflammatory cytokine macrophage migration inhibitory factor (MIF) is a multifunctional cytokine and has been found involved in many neurological diseases such as Alzheimer disease (AD), epilepsy, and multiple sclerosis. Previous studies have shown that MIF is expressed in neocortex, hippocampus, hypothalamus, cerebellum, and spinal cord in adult mice. It is expressed by astrocytes and activates microglias in neuroinflammation. Further studies have shown that MIF is detected in moss fibers of dentate granule cells and in apical dendrites of pyramidal neurons in adult hippocampus. Only NeuroD-positive immature granule neurons but not NeuN-positive mature neurons express MIF. These findings led us eager to know the exact role of MIF in the development of hippocampus. Therefore, we systematically checked the spatial and temporal expression pattern of MIF and characterized MIF-positive cells in hippocampus from mice aged from postnatal day 0 (P0) to 3 months. Our results showed that the lowest level of MIF protein occurred at P7 and mif mRNA increased from P0, reached a peak at P7, and stably expressed until P30 before declining dramatically at 3 months. MIF was localized in fibers of GFAP- and BLBP-positive radial glial precursor cells in dentate gyrus (DG). DCX-expressing newly generated neurons were MIF-negative. Inhibition of MIF by MIF antagonist S, R-3-(4-hydroxyphenyl)-4, 5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) reduced BrdU-positive cells. Interestingly, MIF was expressed by NeuN-positive GABAergic interneurons including parvalbumin-and Reelin-expressing cells in the DG. Neither NeuN-positive granule cells nor NeuN-positive pyramidal neurons expressed MIF. In transgenic mice, POMC-EGFP–positive immature dentate granule cells and Thy1-EGFP–positive mature granule cells were MIF-negative. Treatment of neuronal cultures with ISO-1 inhibited neurite outgrowth. Therefore, we conclude that MIF might be important for feature maintenance of neural stem cells and neurite outgrowth during hippocampal development.

促炎细胞因子巨噬细胞迁移抑制因子（MIF）是一种多功能细胞因子，已发现它与许多神经系统疾病有关，例如阿尔茨海默病（AD），癫痫病和多发性硬化症。先前的研究表明，成年小鼠的新皮层，海马，下丘脑，小脑和脊髓中均表达MIF。它由星形胶质细胞表达并激活神经炎症中的小胶质细胞。进一步的研究表明，在成年海马的齿状颗粒细胞的苔藓纤维和锥体神经元的顶端树突中检测到MIF。仅NeuroD阳性未成熟颗粒神经元表达，而NeuN阳性成熟神经元则不表达MIF。这些发现使我们渴望知道MIF在海马发育中的确切作用。因此，我们系统地检查了出生后第0天（P0）至3个月大的小鼠海马中MIF的时空表达模式并表征了MIF阳性细胞。我们的结果表明，最低水平的MIF蛋白发生在P7和熟女mRNA从P0开始增加，在P7达到峰值，并稳定表达直至P30，然后在3个月时急剧下降。MIF位于齿状回（DG）的GFAP和BLBP阳性放射状胶质前体细胞的纤维中。表达DCX的新生神经元MIF阴性。MIF拮抗剂S，R-3-（4-羟苯基）-4、5-二氢-5-异恶唑乙酸甲酯（ISO-1）对MIF的抑制作用可降低BrdU阳性细胞。有趣的是，MIF是由NeuN阳性的GABA能性中间神经元表达的，包括DG中表达小白蛋白和Reelin的细胞。NeuN阳性颗粒细胞和NeuN阳性锥体神经元均未表达MIF。在转基因小鼠中，POMC-EGFP阳性未成熟齿状颗粒细胞和Thy1-EGFP阳性成熟颗粒细胞为MIF阴性。用ISO-1处理神经元培养物可抑制神经突生长。