Lee Yeunkum, Kang Hyojin, Jin Chunmei, Zhang Yinhua, Kim Yoonhee, Han Kihoon
Department of Neuroscience, College of Medicine, Korea University, Seoul, South Korea.
Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, South Korea.
Anim Cells Syst (Seoul). 2019 Apr 12;23(4):270-274. doi: 10.1080/19768354.2019.1595142. eCollection 2019.
Both deletions and duplications of the SH3 and multiple ankyrin repeat domains 3 () gene, encoding excitatory postsynaptic scaffolds, are causally associated with various brain disorders, suggesting that proper Shank3 dosage is critical for normal brain development and function. In addition to its well-established synaptic functions, recent studies have suggested that Shank3 can also affect gene expression in the nucleus. However, it has not been investigated whether there are a group of genes whose directional expression is regulated in a Shank3 dosage-dependent manner (i.e. showing opposite changes in expression following Shank3 reduction and overexpression). This is an important issue to be examined for better understanding why neuronal development and function are sensitive to Shank3 dosage, and how much transcriptional changes contribute to neuronal phenotypes affected by Shank3 dosage. To examine this, we performed transcriptome analyses on the striatum of heterozygous and knock-out mice, which identified three and 17 differentially expressed genes, respectively. We then compared the results to those of our previous striatal transcriptome analysis of overexpressing mice and identified 31 candidate genes showing directional expression changes in a Shank3 dosage-dependent manner. However, overall, their Shank3 dosage-dependent fold changes were very subtle (average of absolute log2(fold change) was 0.139). Meanwhile, the gene set enrichment analyses of the striatal transcriptome suggested that Shank3 dosage may affect anchoring junction-related functions. Taken together, these results suggest that Shank3 dosage minimally affects directional gene expression changes in the mouse striatum.
编码兴奋性突触后支架的SH3和多个锚蛋白重复结构域3（Shank3）基因的缺失和重复均与多种脑部疾病存在因果关系，这表明适当的Shank3剂量对正常脑发育和功能至关重要。除了其已确定的突触功能外，最近的研究表明，Shank3也可影响细胞核中的基因表达。然而，尚未研究是否存在一组基因，其定向表达受Shank3剂量依赖性调控（即Shank3减少和过表达后表达呈现相反变化）。这是一个需要研究的重要问题，以便更好地理解为什么神经元发育和功能对Shank3剂量敏感，以及转录变化在多大程度上导致受Shank3剂量影响的神经元表型。为了研究这一点，我们对杂合子和基因敲除小鼠的纹状体进行了转录组分析，分别鉴定出3个和17个差异表达基因。然后，我们将结果与之前对Shank3过表达小鼠纹状体转录组分析的结果进行比较，鉴定出31个候选基因，其表达呈现Shank3剂量依赖性的定向变化。然而，总体而言，它们的Shank3剂量依赖性倍数变化非常细微（绝对log2（倍数变化）的平均值为0.139）。同时，纹状体转录组的基因集富集分析表明，Shank3剂量可能影响锚定连接相关功能。综上所述，这些结果表明，Shank3剂量对小鼠纹状体中定向基因表达变化的影响极小。
