Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark ; Department of Neurosurgery, University of Bern, Bern, Switzerland.
PLoS One. 2013 Oct 7;8(10):e76592. doi: 10.1371/journal.pone.0076592. eCollection 2013.
Trefoil factor 1 (TFF1) belongs to a family of secreted peptides with a characteristic tree-looped trefoil structure. TFFs are mainly expressed in the gastrointestinal tract where they play a critical role in the function of the mucosal barrier. TFF1 has been suggested as a neuropeptide, but not much is known about its expression and function in the central nervous system. We investigated the expression of TFF1 in the developing and adult rat midbrain. In the adult ventral mesencephalon, TFF1-immunoreactive (-ir) cells were predominantly found in the substantia nigra pars compacta (SNc), the ventral tegmental area (VTA) and in periaqueductal areas. While around 90% of the TFF1-ir cells in the SNc co-expressed tyrosine hydroxylase (TH), only a subpopulation of the TH-ir neurons expressed TFF1. Some TFF1-ir cells in the SNc co-expressed the calcium-binding proteins calbindin or calretinin and nearly all were NeuN-ir confirming a neuronal phenotype, which was supported by lack of co-localization with the astroglial marker glial fibrillary acidic protein (GFAP). Interestingly, at postnatal (P) day 7 and P14, a significantly higher proportion of TH-ir neurons in the SNc co-expressed TFF1 as compared to P21. In contrast, the proportion of TFF1-ir cells expressing TH remained unchanged during postnatal development. Furthermore, significantly more TH-ir neurons expressed TFF1 in the SNc, compared to the VTA at all four time-points investigated. Injection of the tracer fluorogold into the striatum of adult rats resulted in retrograde labeling of several TFF1 expressing cells in the SNc showing that a significant fraction of the TFF1-ir cells were projection neurons. This was also reflected by unilateral loss of TFF1-ir cells in SNc of 6-hydroxylase-lesioned hemiparkinsonian rats. In conclusion, we show for the first time that distinct subpopulations of midbrain dopaminergic neurons express TFF1, and that this expression pattern is altered in a rat model of Parkinson's disease.
三叶因子 1（TFF1）属于一类具有特征性三叶环树突样结构的分泌肽家族。TFF 主要在胃肠道中表达，在粘膜屏障功能中发挥关键作用。TFF1 已被认为是一种神经肽，但关于其在中枢神经系统中的表达和功能知之甚少。我们研究了 TFF1 在发育中和成年大鼠中脑的表达。在成年大鼠腹侧中脑，TFF1 免疫反应性（-ir）细胞主要存在于黑质致密部（SNc）、腹侧被盖区（VTA）和导水管周围区域。虽然 SNc 中约 90%的 TFF1-ir 细胞共表达酪氨酸羟化酶（TH），但只有 TH-ir 神经元的亚群表达 TFF1。SNc 中的一些 TFF1-ir 细胞共表达钙结合蛋白 calbindin 或 calretinin，几乎所有细胞都 NeuN-ir，证实了神经元表型，这一表型由缺乏与星形胶质细胞标志物胶质纤维酸性蛋白（GFAP）的共定位得到支持。有趣的是，与 P21 相比，在 P7 和 P14 时，SNc 中 TH-ir 神经元共表达 TFF1 的比例明显更高。相比之下，在出生后发育过程中，TFF1-ir 细胞表达 TH 的比例保持不变。此外，在所有四个研究时间点，SNc 中 TH-ir 神经元表达 TFF1 的比例明显高于 VTA。将示踪剂荧光金注入成年大鼠纹状体后，导致 SNc 中几个表达 TFF1 的细胞逆行标记，表明 TFF1-ir 细胞的一个显著部分是投射神经元。这也反映在 6-羟多巴胺酶损伤的半帕金森大鼠 SNc 中 TFF1-ir 细胞的单侧缺失。总之，我们首次表明，中脑多巴胺能神经元的不同亚群表达 TFF1，并且这种表达模式在帕金森病大鼠模型中发生改变。
