Molecular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan.
J Neurochem. 2011 Jul;118(1):45-56. doi: 10.1111/j.1471-4159.2011.07287.x. Epub 2011 May 19.
Although epidermal growth factor (EGF) receptor (ErbB1) is implicated in Parkinson's disease and schizophrenia, the neurotrophic action of ErbB1 ligands on nigral dopaminergic neurons remains controversial. Here, we ascertained colocalization of ErbB1 and tyrosine hydroxylase (TH) immunoreactivity and then characterized the neurotrophic effects of ErbB1 ligands on this cell population. In mesencephalic culture, EGF and glial-derived neurotrophic factor (GDNF) similarly promoted survival and neurite elongation of dopaminergic neurons and dopamine uptake. The EGF-promoted dopamine uptake was not inhibited by GDNF-neutralizing antibody or TrkB-Fc, whereas EGF-neutralizing antibody fully blocked the neurotrophic activity of the conditioned medium that was prepared from EGF-stimulated mesencephalic cultures. The neurotrophic action of EGF was abolished by ErbB1 inhibitors and genetic disruption of erbB1 in culture. In vivo administration of ErbB1 inhibitors to rat neonates diminished TH and dopamine transporter (DAT) levels in the striatum and globus pallidus but not in the frontal cortex. In parallel, there was a reduction in the density of dopaminergic varicosities exhibiting intense TH immunoreactivity. In agreement, postnatal erbB1-deficient mice exhibited similar decreases in TH levels. Although neurotrophic supports to dopaminergic neurons are redundant, these results confirm that ErbB1 ligands contribute to the phenotypic and functional development of nigral dopaminergic neurons.
尽管表皮生长因子（EGF）受体（ErbB1）与帕金森病和精神分裂症有关，但 ErbB1 配体对黑质多巴胺能神经元的神经营养作用仍存在争议。在这里，我们确定了 ErbB1 和酪氨酸羟化酶（TH）免疫反应的共定位，然后表征了 ErbB1 配体对该细胞群的神经营养作用。在中脑培养物中，EGF 和胶质细胞衍生的神经营养因子（GDNF）同样促进多巴胺能神经元的存活和突起伸长以及多巴胺摄取。EGF 促进的多巴胺摄取不受 GDNF 中和抗体或 TrkB-Fc 的抑制，而 EGF 中和抗体完全阻断了从 EGF 刺激的中脑培养物制备的条件培养基的神经营养活性。在培养物中，ErbB1 抑制剂和 erbB1 的基因缺失消除了 EGF 的神经营养作用。在新生大鼠体内给予 ErbB1 抑制剂会降低纹状体和苍白球中的 TH 和多巴胺转运蛋白（DAT）水平，但不会降低前额皮质中的水平。平行地，表现出强烈 TH 免疫反应的多巴胺能囊泡的密度降低。同样，出生后 erbB1 缺陷型小鼠也表现出类似的 TH 水平降低。尽管多巴胺能神经元的神经营养支持是冗余的，但这些结果证实 ErbB1 配体有助于黑质多巴胺能神经元的表型和功能发育。
