Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA.
J Neurosci. 2011 Aug 10;31(32):11437-42. doi: 10.1523/JNEUROSCI.0181-11.2011.
Autism spectrum disorder (ASD) is a highly heritable, behaviorally defined, heterogeneous disorder of unknown pathogenesis. Several genetic risk genes have been identified, including the gene encoding the receptor tyrosine kinase MET, which regulates neuronal differentiation and growth. An ASD-associated polymorphism disrupts MET gene transcription, and there are reduced levels of MET protein expression in the mature temporal cortex of subjects with ASD. To address the possible neurodevelopmental contribution of MET to ASD pathogenesis, we examined the expression and transcriptional regulation of MET by a transcription factor, FOXP2, which is implicated in regulation of cognition and language, two functions altered in ASD. MET mRNA expression in the midgestation human fetal cerebral cortex is strikingly restricted, localized to portions of the temporal and occipital lobes. Within the cortical plate of the temporal lobe, the pattern of MET expression is highly complementary to the expression pattern of FOXP2, suggesting the latter may play a role in repression of gene expression. Consistent with this, MET and FOXP2 also are reciprocally expressed by differentiating normal human neuronal progenitor cells (NHNPs) in vitro, leading us to assess whether FOXP2 transcriptionally regulates MET. Indeed, FOXP2 binds directly to the 5' regulatory region of MET, and overexpression of FOXP2 results in transcriptional repression of MET. The expression of MET in restricted human neocortical regions, and its regulation in part by FOXP2, is consistent with genetic evidence for MET contributing to ASD risk.
自闭症谱系障碍（ASD）是一种高度遗传、行为定义、异质性的疾病，其发病机制尚不清楚。已经确定了几个遗传风险基因，包括编码受体酪氨酸激酶 MET 的基因，该基因调节神经元分化和生长。与 ASD 相关的基因多态性破坏了 MET 基因的转录，ASD 患者的成熟颞叶皮质中 MET 蛋白的表达水平降低。为了研究 MET 对 ASD 发病机制的可能神经发育贡献，我们研究了转录因子 FOXP2 对 MET 的表达和转录调节作用，FOXP2 与认知和语言的调节有关，这两种功能在 ASD 中发生改变。中孕期人类胎儿大脑皮质中 MET mRNA 的表达受到显著限制，局限于颞叶和枕叶的部分区域。在颞叶皮质的皮质板中，MET 表达的模式与 FOXP2 的表达模式高度互补，表明后者可能在抑制基因表达中发挥作用。与此一致，MET 和 FOXP2 也在体外分化的正常人类神经祖细胞（NHNP）中相互表达，这促使我们评估 FOXP2 是否转录调节 MET。事实上，FOXP2 直接结合 MET 的 5'调控区，FOXP2 的过表达导致 MET 的转录抑制。MET 在人类新皮质的受限区域的表达及其部分受 FOXP2 调节的情况与 MET 对 ASD 风险有贡献的遗传证据一致。
