Regulation of MET by FOXP2, genes implicated in higher cognitive dysfunction and autism risk.
Regulation of MET by FOXP2, genes implicated in higher cognitive dysfunction and autism risk.
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DOI：
10.1523/jneurosci.0181-11.2011
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发表时间：
2011-08-10
期刊：
影响因子：
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通讯作者：
Geschwind DH
中科院分区：
文献类型：
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作者：
Mukamel Z;Konopka G;Wexler E;Osborn GE;Dong H;Bergman MY;Levitt P;Geschwind DH
自闭症谱系障碍（ASD）是一种高度遗传的，行为定义的，异质性疾病的未知发病机制。已经鉴定出几种遗传风险基因，包括编码调节神经元分化和生长的受体酪氨酸激酶MET的基因。ASD相关的多态性破坏MET基因转录，并且患有ASD的受试者的成熟颞叶皮层中MET蛋白表达水平降低。为了解决MET对ASD发病机制的可能神经发育贡献，我们研究了MET通过转录因子FOXP2的表达和转录调节，FOXP2涉及认知和语言的调节，这两种功能在ASD中改变。妊娠中期人胎儿大脑皮层中MET mRNA的表达明显受限，局限于颞叶和枕叶的部分区域。在颞叶皮质板中，MET的表达模式与FOXP2的表达模式高度互补，表明后者可能在抑制基因表达中起作用。与此相一致，MET和FOXP2也通过体外分化正常人神经元祖细胞（NHNP）而表达，这使我们评估FOXP2是否转录调节MET。事实上，FOXP2直接与MET的5′调控区结合，并且FOXP2的过表达导致MET的转录抑制。MET在有限的人类新皮层区域的表达，以及FOXP2对其的部分调节，与MET导致ASD风险的遗传证据一致。
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. With in 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.