Disruption of cerebral cortex MET signaling in autism spectrum disorder
Disruption of cerebral cortex MET signaling in autism spectrum disorder
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DOI：
10.1002/ana.21180
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发表时间：
2007-09-01
影响因子：
11.2
通讯作者：
Persico, Antonio M.
中科院分区：
文献类型：
--
作者：
Campbell, Daniel B.;D'Oronzio, Rosanna;Persico, Antonio M.
目的：自闭症谱系障碍（ASD）的易感性与多基因有关。一个特别有希望的候选基因是MET基因，其编码受体酪氨酸激酶，该受体酪氨酸激酶介导脑回路形成、免疫功能和胃肠道修复中的肝细胞生长因子（HGF）信号传导。MET启动子变体rs 1858830等位基因“C”与ASD密切相关，并导致基因转录降低。在这里，我们研究了MET和MET信号通路的成员在死后的ASD病例和健康对照subjects.Methods：蛋白质，总RNA，和DNA的表达水平从死后的颞叶皮层灰质样本（BA 41/42，52，或22）属于8对ASD病例和匹配的对照组。结果：与对照组相比，ASD组MET蛋白表达水平明显降低，而对照组MET蛋白表达水平明显降低，差异有统计学意义（P <0.05）。这伴随着ASD大脑中参与调节MET信号传导活性的蛋白质的信使RNA表达增加。MET和HGF的共表达分析表明，在ASD cases.Interpretation中被破坏的对照受试者中呈正相关：MET和相关分子的表达改变表明信号转导失调，可能有助于ASD中电路形成和功能的改变。编码参与MET激活的蛋白质的基因的互补似乎经历了表达的长期代偿性变化，这可能是ASD病理生理学的标志性贡献。
Objective: Multiple genes contribute to autism spectrum disorder (ASD) susceptibility. One particularly promising candidate is the MET gene, which encodes a receptor tyrosine kinase that mediates hepatocyte growth factor (HGF) signaling in brain circuit formation, immune function, and gastrointestinal repair. The MET promoter variant rs1858830 allele "C" is strongly associated with ASD and results in reduced gene transcription. Here we examined expression levels of MET and members of the MET signaling pathway in postmortem cerebral cortex from ASD cases and healthy control subjects.Methods: Protein, total RNA, and DNA were extracted from postmortem temporal cortex gray matter samples (BA 41/42, 52, or 22) belonging to eight pairs of ASD cases and matched control subjects. MET protein expression was determined by Western blotting; messenger RNA expression of MET and other related transcripts was assayed by microarray and quantitative reverse transcriptase polymerase chain reaction.Results: MET protein levels were significantly decreased in ASD cases compared with control Subjects. This was accompanied in ASD brains by increased messenger RNA expression for proteins involved in regulating MET signaling activity. Analyses of coexpression of MET and HGF demonstrated a positive correlation in control subjects that was disrupted in ASD cases.Interpretation: Altered expression of MET and related molecules suggests dysregulation of signaling that may contribute to altered circuit formation and function in ASD. The complement of genes that encode proteins involved in MET activation appears to undergo long-term compensatory changes in expression that may be a hallmark contribution to the pathophysiology of ASD.