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在Engrailed-2基因敲除小鼠的前脑中,脑源性神经营养因子信号传导发生改变。

Brain-derived neurotrophic factor signaling is altered in the forebrain of Engrailed-2 knockout mice.

作者信息

Zunino G, Messina A, Sgadò P, Baj G, Casarosa S, Bozzi Y

机构信息

Laboratory of Molecular Neuropathology, Centre for Integrative Biology, University of Trento, Italy.

Laboratory of Developmental Neurobiology, Centre for Integrative Biology, University of Trento, Italy.

出版信息

Neuroscience. 2016 Jun 2;324:252-61. doi: 10.1016/j.neuroscience.2016.03.023. Epub 2016 Mar 14.

Abstract

Engrailed-2 (En2), a homeodomain transcription factor involved in regionalization and patterning of the midbrain and hindbrain regions has been associated to autism spectrum disorders (ASDs). En2 knockout (En2(-/-)) mice show ASD-like features accompanied by a significant loss of GABAergic subpopulations in the hippocampus and neocortex. Brain-derived neurotrophic factor (BDNF) is a crucial factor for the postnatal development of forebrain GABAergic neurons, and altered GABA signaling has been hypothesized to underlie the symptoms of ASD. Here we sought to determine whether interneuron loss in the En2(-/-) forebrain might be related to altered expression of BDNF and its signaling receptors. We first evaluated the expression of different BDNF mRNA isoforms in the neocortex and hippocampus of wild-type (WT) and En2(-/-) mice. Quantitative RT-PCR showed a marked down-regulation of several splicing variants of BDNF mRNA in the neocortex but not hippocampus of adult En2(-/-) mice, as compared to WT controls. Accordingly, levels of mature BDNF protein were lower in the neocortex but not hippocampus of En2(-/-) mice, as compared to WT. Increased levels of phosphorylated TrkB and decreased levels of p75 receptor were also detected in the neocortex of mutant mice. Accordingly, the expression of low density lipoprotein receptor (LDLR) and RhoA, two genes regulated via p75 was significantly altered in forebrain areas of mutant mice. These data indicate that BDNF signaling alterations might be involved in the anatomical changes observed in the En2(-/-) forebrain and suggest a pathogenic role of altered BDNF signaling in this mouse model of ASD.

摘要

Engrailed-2(En2)是一种参与中脑和后脑区域分化及模式形成的同源结构域转录因子,已被发现与自闭症谱系障碍(ASD)有关。En2基因敲除(En2(-/-))小鼠表现出类似ASD的特征,同时海马体和新皮质中的γ-氨基丁酸能亚群显著减少。脑源性神经营养因子(BDNF)是前脑γ-氨基丁酸能神经元出生后发育的关键因素,并且有人推测γ-氨基丁酸信号改变是ASD症状的基础。在这里,我们试图确定En2(-/-)前脑中的中间神经元缺失是否可能与BDNF及其信号受体的表达改变有关。我们首先评估了野生型(WT)和En2(-/-)小鼠新皮质和海马体中不同BDNF mRNA亚型的表达。定量逆转录聚合酶链反应(RT-PCR)显示,与野生型对照相比,成年En2(-/-)小鼠新皮质中BDNF mRNA的几种剪接变体显著下调,但海马体中没有。相应地,与野生型相比,En2(-/-)小鼠新皮质中成熟BDNF蛋白水平较低,但海马体中没有。在突变小鼠的新皮质中还检测到磷酸化TrkB水平升高和p75受体水平降低。相应地,通过p75调节的两个基因低密度脂蛋白受体(LDLR)和RhoA的表达在突变小鼠的前脑区域显著改变。这些数据表明,BDNF信号改变可能参与了En2(-/-)前脑中观察到的解剖学变化,并提示BDNF信号改变在这种ASD小鼠模型中的致病作用。

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