Zhang Muxian, Zhou Yunqiang, Jiang Yiru, Lu Zhancheng, Xiao Xiaoxia, Ning Jinhuan, Sun Hao, Zhang Xian, Luo Hong, Can Dan, Lu Jinsheng, Xu Huaxi, Zhang Yun-Wu
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute for Neuroscience, School of Medicine, Xiamen University, Xiamen, China.
Emergency Department, Xiang'an Hospital, Xiamen University, Xiamen, China.
Front Cell Dev Biol. 2021 Jul 6;9:669798. doi: 10.3389/fcell.2021.669798. eCollection 2021.
Many neurological disorders exhibit sex differences and sex-specific therapeutic responses. Unfortunately, significant amounts of studies investigating molecular and cellular mechanisms underlying these neurological disorders use primary cell cultures with undetermined sexes; and this may be a source for contradictory results among different studies and impair the validity of study conclusion. Herein, we comprehensively compared sexual dimorphism of gene expression in primary neurons, astrocytes, and microglia derived from neonatal mouse brains. We found that overall sexually dimorphic gene numbers were relatively low in these primary cells, with microglia possessing the most (264 genes), neurons possessing the medium (69 genes), and astrocytes possessing the least (30 genes). KEGG analysis indicated that sexually dimorphic genes in these three cell types were strongly enriched for the immune system and immune-related diseases. Furthermore, we identified that sexually dimorphic genes shared by these primary cells dominantly located on the Y chromosome, including , , , and . Finally, we demonstrated that overexpression of increased synaptic transmission specifically in male neurons and caused autism-like behaviors specifically in male mice. Together, our results demonstrate that the sex of primary cells should be considered when these cells are used for studying the molecular mechanism underlying neurological disorders with sex-biased susceptibility, especially those related to immune dysfunction. Moreover, our findings indicate that dysregulation of sexually dimorphic genes on the Y chromosome may also result in autism and possibly other neurological disorders, providing new insights into the genetic driver of sex differences in neurological disorders.
许多神经系统疾病表现出性别差异和性别特异性治疗反应。不幸的是，大量研究神经系统疾病潜在分子和细胞机制的研究使用的是性别未确定的原代细胞培养物；这可能是不同研究结果相互矛盾的一个原因，并损害研究结论的有效性。在此，我们全面比较了源自新生小鼠大脑的原代神经元、星形胶质细胞和小胶质细胞中基因表达的性别二态性。我们发现，这些原代细胞中总体性别二态性基因数量相对较少，其中小胶质细胞最多（264个基因），神经元次之（69个基因），星形胶质细胞最少（30个基因）。KEGG分析表明，这三种细胞类型中的性别二态性基因在免疫系统和免疫相关疾病方面高度富集。此外，我们确定这些原代细胞共有的性别二态性基因主要位于Y染色体上，包括 、 、 和 。最后，我们证明 的过表达特异性地增加了雄性神经元的突触传递，并在雄性小鼠中引发了自闭症样行为。总之，我们的结果表明，当使用这些细胞研究具有性别偏向易感性的神经系统疾病的分子机制时，尤其是那些与免疫功能障碍相关的疾病时，应考虑原代细胞的性别。此外，我们的研究结果表明，Y染色体上性别二态性基因的失调也可能导致自闭症以及可能的其他神经系统疾病，为神经系统疾病中性别差异的遗传驱动因素提供了新的见解。
