Lee Seungjoon, Kang Hyojin, Jung Hwajin, Kim Eunjoon, Lee Eunee
Department of Biological Sciences, Korea Advanced Institute for Science and Technology (KAIST), Daejeon, South Korea.
Division of National Supercomputing, KISTI, Daejeon, South Korea.
Front Mol Neurosci. 2021 Jun 11;14:683196. doi: 10.3389/fnmol.2021.683196. eCollection 2021.
Shank2 is an abundant postsynaptic scaffolding protein that is known to regulate excitatory synapse assembly and synaptic transmission and has been implicated in various neurodevelopmental disorders, including autism spectrum disorders (ASD). Previous studies on -mutant mice provided mechanistic insights into their autistic-like phenotypes, but it remains unclear how transcriptomic patterns are changed in brain regions of the mutant mice in age- and gene dosage-dependent manners. To this end, we performed RNA-Seq analyses of the transcripts from the prefrontal cortex (PFC) of heterozygous and homozygous -mutant mice lacking exons 6 and 7 at juvenile (week 3) and adult (week 12) stages. Juvenile heterozygous -mutant mice showed upregulation of glutamate synapse-related genes, downregulation of ribosomal and mitochondrial genes, and transcriptomic changes that are opposite to those observed in ASD (anti-ASD) such as upregulation of ASD_down (downregulated in ASD), GABA neuron-related, and oligodendrocyte-related genes. Juvenile homozygous mice showed upregulation of chromatin-related genes and transcriptomic changes that are in line with those occurring in ASD (pro-ASD) such as downregulation of ASD_down, GABA neuron-related, and oligodendrocyte-related genes. Adult heterozygous and homozygous -mutant mice both exhibited downregulation of ribosomal and mitochondrial genes and pro-ASD transcriptomic changes. Therefore, the gene dosage- and age-dependent effects of deletions in mice include differential transcriptomic changes across distinct functional contexts, including synapses, chromatin, ribosomes, mitochondria, GABA neurons, and oligodendrocytes.
Shank2是一种丰富的突触后支架蛋白，已知其可调节兴奋性突触组装和突触传递，并与包括自闭症谱系障碍（ASD）在内的各种神经发育障碍有关。先前对突变小鼠的研究为其自闭症样表型提供了机制性见解，但尚不清楚突变小鼠脑区的转录组模式如何以年龄和基因剂量依赖性方式发生变化。为此，我们对在幼年（第3周）和成年（第12周）阶段缺失外显子6和7的杂合和纯合突变小鼠前额叶皮质（PFC）的转录本进行了RNA测序分析。幼年杂合突变小鼠表现出谷氨酸突触相关基因上调、核糖体和线粒体基因下调，以及与ASD中观察到的相反的转录组变化（抗ASD），如ASD_down（在ASD中下调）、GABA神经元相关和少突胶质细胞相关基因上调。幼年纯合小鼠表现出染色质相关基因上调以及与ASD中发生的一致的转录组变化（促ASD），如ASD_down、GABA神经元相关和少突胶质细胞相关基因下调。成年杂合和纯合突变小鼠均表现出核糖体和线粒体基因下调以及促ASD转录组变化。因此，小鼠中缺失的基因剂量和年龄依赖性效应包括跨不同功能背景的差异转录组变化，包括突触、染色质、核糖体、线粒体、GABA神经元和少突胶质细胞。
