Modeling the functional genomics of autism using human neurons.
Modeling the functional genomics of autism using human neurons.
复制标题
使用人神经元对自闭症的功能基因组学进行建模。
DOI：
10.1038/mp.2011.60
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发表时间：
2012-02
影响因子：
11
通讯作者：
Geschwind DH
中科院分区：
文献类型：
--
作者：
Konopka G;Wexler E;Rosen E;Mukamel Z;Osborn GE;Chen L;Lu D;Gao F;Gao K;Lowe JK;Geschwind DH
来自各种来源的人类神经祖细胞为体外模拟人类神经精神疾病的各个方面提供了新的机会。这种体外模型具有人类遗传背景的优点，再加上快速且易于操作，使其成为动物模型的非常有用的辅助手段。在这里，我们研究了是否可以利用人类神经元培养系统来评估与人类神经分化有关的转录程序以及对神经发育障碍（例如自闭症）的一些分子特征进行建模。通过添加特定的生长因子，原代正常人类神经祖细胞（NHNP）分化为有丝分裂后神经元状态，并在神经元分化的整个时间过程中检查全基因组基因表达。经过四个星期的分化后，大量与自闭症谱系障碍（ASD）相关的基因要么被诱导，要么被抑制。其中包括 ASD 易感基因 neurexin 1，该基因在体外表现出与 neurexin 3 不同的模式，我们在胎儿人脑中对其进行了体内验证。使用加权基因共表达网络分析（WGCNA），我们可视化了转录调控的网络结构，通过这种无偏分析证明，大量 ASD 候选基因在分化过程中受到协调调控。由于 NHNP 在遗传上易于处理和操作，因此它们可用于研究多个 ASD 候选基因突变对神经元分化和基因表达的影响，以及潜在治疗分子的影响。这些数据还为更好地了解自闭症谱系障碍中被破坏的信号通路提供了一步。
Human neural progenitors from a variety of sources present new opportunities to model aspects of human neuropsychiatric disease in vitro. Such in vitro models provide the advantages of a human genetic background, combined with rapid and easy manipulation, making them highly useful adjuncts to animal models. Here, we examined whether a human neuronal culture system could be utilized to assess the transcriptional program involved in human neural differentiation and in modeling some of the molecular features of a neurodevelopmental disorder, such as autism. Primary normal human neuronal progenitors (NHNPs) were differentiated into a post-mitotic neuronal state through addition of specific growth factors and whole-genome gene expression was examined throughout a time course of neuronal differentiation. After four weeks of differentiation, a significant number of genes associated with autism spectrum disorders (ASD) are either induced or repressed. This includes the ASD susceptibility gene neurexin 1, which showed a distinct pattern from neurexin 3 in vitro, and which we validated in vivo in fetal human brain. Using weighted gene co-expression network analysis (WGCNA), we visualized the network structure of transcriptional regulation, demonstrating via this unbiased analysis that a significant number of ASD candidate genes are coordinately regulated during the differentiation process. Since NHNPs are genetically tractable and manipulable, they can be used to study both the effects of mutations in multiple ASD candidate genes on neuronal differentiation and gene expression in combination with the effects of potential therapeutic molecules. These data also provide a step towards better understanding of the signaling pathways disrupted in ASD.
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影响因子：
64.8
作者：
Cook, Edwin H., Jr.;Scherer, Stephen W.
通讯作者：
Scherer, Stephen W.
影响因子：
4
作者：
Bill, Brent R.;Geschwind, Daniel H.
通讯作者：
Geschwind, Daniel H.
影响因子：
3.3
作者：
ENG, LF
通讯作者：
ENG, LF
DOI：
10.1196/annals.1377.001
发表时间：
2006-01-01
期刊：
INTEGRATED MOLECULAR MEDICINE FOR NEURONAL AND NEOPLASTIC DISORDERS
影响因子：
--
作者：
Bailey, Jason A.;Lahiri, Debomoy K.
通讯作者：
Lahiri, Debomoy K.
影响因子：
2.7
作者：
Hilario, Jona D.;Rodino-Klapac, Louise R.;Beattie, Christine E.
通讯作者：
Beattie, Christine E.