Department of Neuroscience, College of Medicine, Korea University, 73, Inchon-ro, Seongbuk-gu, Seoul, 02841, South Korea.
Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, 02841, South Korea.
Mol Brain. 2018 Nov 27;11(1):71. doi: 10.1186/s13041-018-0413-4.
Various mutations in the SH3 and multiple ankyrin repeat domains 3 (SHANK3) gene are associated with neurodevelopmental and neuropsychiatric disorders. Thus far, synaptic abnormalities in multiple brain regions, including the hippocampus, prefrontal cortex, striatum, and ventral tegmental area, have been investigated in several lines of Shank3 mutant mice. However, although some reports have shown loss and gain of body weight in Shank3 knock-out and overexpressing transgenic (TG) mice, respectively, the potential functions of Shank3 in the hypothalamus, a brain region critically involved in energy intake and expenditure, are unknown. Hence, we first characterized endogenous Shank3 mRNA and protein expression in the hypothalamus of adult wild-type mice. Thereafter, we performed transcriptome analysis (RNA-sequencing) in the hypothalamus of adult Shank3 TG mice which mildly overexpress Shank3 proteins. By comparing the 174 differentially expressed genes in the hypothalamus with those previously reported in the striatum and medial prefrontal cortex (mPFC) of Shank3 TG mice, we found that 159 were hypothalamus-specific while only 15 were also observed in either the striatum or mPFC. Furthermore, gene set enrichment analysis of the RNA-sequencing analysis revealed that ribosome-related genes were enriched especially in the up-regulated genes of Shank3 TG hypothalamus, which is in contrast to the results of the Shank3 TG striatum and mPFC analyses, where ribosome-related genes were enriched in the down-regulated genes. Beyond revealing endogenous Shank3 mRNA and protein expression in the hypothalamus, our results suggest unique molecular changes in the hypothalamus of Shank3 TG mice compared with those in the striatum and mPFC.
各种 SH3 和多个锚重复域 3（SHANK3）基因突变与神经发育和神经精神疾病有关。迄今为止，已经在几种 Shank3 突变小鼠中研究了多个脑区的突触异常，包括海马体、前额叶皮层、纹状体和腹侧被盖区。然而，尽管一些报道显示 Shank3 敲除和过表达转基因（TG）小鼠分别出现体重减轻和增加，但 Shank3 在参与能量摄入和消耗的大脑区域下丘脑中的潜在功能尚不清楚。因此，我们首先在成年野生型小鼠的下丘脑内表征内源性 Shank3 mRNA 和蛋白质表达。此后，我们在轻度过表达 Shank3 蛋白的成年 Shank3 TG 小鼠的下丘脑内进行了转录组分析（RNA 测序）。通过将下丘脑的 174 个差异表达基因与 Shank3 TG 小鼠纹状体和内侧前额叶皮层（mPFC）中先前报道的基因进行比较，我们发现 159 个是下丘脑特异性的，而只有 15 个在纹状体或 mPFC 中也有观察到。此外，RNA 测序分析的基因集富集分析显示核糖体相关基因在 Shank3 TG 下丘脑的上调基因中特别富集，这与 Shank3 TG 纹状体和 mPFC 分析的结果形成对比，在这些分析中，核糖体相关基因在下调基因中富集。除了揭示下丘脑内的内源性 Shank3 mRNA 和蛋白质表达外，我们的结果还表明，与纹状体和 mPFC 相比，Shank3 TG 小鼠的下丘脑存在独特的分子变化。
