Gene expression in striatums of Foxp2-hum, Foxp2-ko and wild-type mice

It has been proposed that two amino acid substitutions in the transcription factor FOXP2 have been positively selected during human evolution due to effects on aspects of speech and language. Here, we introduce these substitutions into the endogenous Foxp2 gene.of mice. Although these mice are generally healthy, they have qualitatively different ultrasonic vocalizations, decreased exploratory behavior and decreased dopamine concentrations in the brain suggesting an effect of the humanized Foxp2 allele on basal ganglia. In the striatum, a part of the basal ganglia that is affected in humans with a speech deficit due to one non-functional FOXP2 allele, we find that medium spiny neurons have increased dendrite lengths and increased synaptic plasticity. Since mice carrying one non-functional Foxp2 allele show opposite effects, this suggests that alterations in cortico-basal ganglia circuits might have been important for the evolution of speech and language in humans. In this particular experiment, we investigate the effects of human Foxp2 (Foxp2hum) and the non-functional Foxp2 allele on striatal gene expression in embryonic, young and adult mice. We determined genome-wide gene expression patterns in striatal biopsies from Foxp2hum/hum, Foxp2wt/ko and Foxp2wt/wt mice using high-density oligonucleotide arrays. The animals were derived from two independent FoxP2 knock-in strains and one knock-out strain. In total 71 animals were used, 29 males and 42 females. The mice ages were E16.5, P15, P18, P21 and P95 when sacrificed. The microarrays were processed in totally six batches.有研究提出，转录因子FOXP2（transcription factor FOXP2）的两个氨基酸替换位点在人类演化过程中受到正向选择，这一选择源于其对言语与语言相关特征的影响。在此，我们将这两个氨基酸替换引入小鼠的内源性Foxp2基因中。尽管这些小鼠整体健康状况良好，但它们的超声发声（ultrasonic vocalizations）出现了质性差异，探索行为减弱，且脑部多巴胺浓度降低，这表明人源化Foxp2等位基因（humanized Foxp2 allele）对基底神经节（basal ganglia）存在影响。在纹状体（striatum）——这是基底神经节的组成部分，在携带一个功能丧失型FOXP2等位基因的言语缺陷人类患者中会受到累及——中，我们发现中型多棘神经元（medium spiny neurons）的树突长度增加，突触可塑性（synaptic plasticity）增强。由于携带一个功能丧失型Foxp2等位基因的小鼠表现出相反的表型，这提示皮层-基底神经节环路（cortico-basal ganglia circuits）的改变可能在人类言语与语言演化中发挥了关键作用。在本项特定实验中，我们探究了人源Foxp2（Foxp2hum）与功能丧失型Foxp2等位基因对胚胎期、青年期及成年小鼠纹状体基因表达的影响。我们使用高密度寡核苷酸芯片（high-density oligonucleotide arrays），对Foxp2hum/hum、Foxp2wt/ko及Foxp2wt/wt小鼠的纹状体活检样本进行了全基因组基因表达谱分析。实验动物来源于两个独立的FoxP2基因敲入（knock-in）品系与一个基因敲除（knock-out）品系。本次实验共使用71只动物，其中雄性29只，雌性42只。小鼠在处死时的年龄分别为胚胎期16.5天（E16.5）、出生后第15天（P15）、第18天（P18）、第21天（P21）以及第95天（P95）。芯片实验共分为6个批次进行处理。