Zbtb16 regulates social cognitive behaviors and neocortical development

Recent genomic studies suggest that a single gene is involved in multiple diseases, however it is unclear what mechanism destined for different diseases by a single gene. Mutations of ZBTB16 are associated with autism spectrum disorder (ASD) and schizophrenia (SCZ), but how ZBTB16 fates ASD or SCZ are unknown. Here we show the deletion of Zbtb16 in mice leads to both ASD- and SCZ-like behaviors such as social impairment, repetitive behaviors, risk-taking behaviors, and cognitive impairment. To elucidate the mechanism underlying the behavioral phenotypes, we carried out histological studies and observed impairments in thinning of neocortical layer 6 (L6) and a reduction of TBR1+ neurons in the prefrontal cortex (PFC) of Zbtb16 KO mice. Furthermore, we found increased dendritic spines and microglia as well as developmental defects in oligodendrocytes and neocortical myelination in the PFC of Zbtb16 KO mice. Using a genomics approach, we identified the Zbtb16-transcriptome that includes genes involved in both ASD and SCZ pathophysiology and neocortical maturation such as neurogenesis and myelination. Co-expression networks further identified Zbtb16-correlated modules that are unique to ASD or SCZ respectively. Our study provides insight into the differential role of the single gene ZBTB16 in ASD and SCZ. Zbtb16 KO and wild-type mice at 7 weeks age were used. Each group contains 5 mice. RNA-seq were conducted using RNAs extracted from prefrontal cortex of these mice.近年来的基因组学研究表明，单个基因可参与多种疾病的发生发展，但目前尚不清楚单个基因引发不同疾病的具体作用机制。ZBTB16基因的突变与自闭症谱系障碍（autism spectrum disorder, ASD）及精神分裂症（schizophrenia, SCZ）相关，但ZBTB16如何决定个体罹患ASD或SCZ的机制仍不明确。本研究发现，小鼠体内Zbtb16基因的敲除可引发类ASD及类SCZ的行为表型，包括社交障碍、重复行为、冒险行为及认知功能受损。为阐明该行为表型背后的分子机制，我们开展了组织学研究，观察到Zbtb16敲除（knockout, KO）小鼠的新皮质第6层（neocortical layer 6, L6）出现变薄现象，且前额叶皮层（prefrontal cortex, PFC）内的TBR1阳性神经元数量减少。此外，我们还发现Zbtb16 KO小鼠前额叶皮层内的树突棘与小胶质细胞数量增多，同时存在少突胶质细胞发育缺陷及新皮质髓鞘形成异常。我们通过基因组学分析手段，鉴定出Zbtb16相关转录组（transcriptome），其中包含参与ASD与SCZ病理生理过程以及新皮质成熟（如神经发生、髓鞘形成）的相关基因。共表达网络（co-expression networks）分析进一步发现，与Zbtb16相关的基因模块分别特异性对应ASD或SCZ。本研究为解析单个基因ZBTB16在ASD与SCZ中发挥的差异化作用提供了新的见解。本研究使用7周龄的Zbtb16敲除小鼠与野生型小鼠，每组各5只。我们从这些小鼠的前额叶皮层中提取RNA，开展了RNA测序（RNA-seq）实验。