Long-term impact of placental allopregnanolone insufficiency on the mouse transcriptome of cerebral cortex, hippocampus, hypothalamus and cerebellum

Goal: To test the long-term influence of placental allopregnanolone (ALLO) loss on mouse brain transcriptome, in a sex- and region-specficic manner. Methods: We deleted the gene encoding the synthetic enzyme for ALLO (Akr1c14) specifically in trophoblasts by crossing Akr1c14-floxed mice with Cyp19a-Cre mice (plKO mice). Region-specific mRNA profiles of 30-day old WT and plKO mice were generated by 3'mRNA sequencing, in triplicate, using Illumina HiSeq 2500. Results: Our RNA sequencing analysis reveals that placental ALLO withdrawal is associated with region- and sex-specific gene expression changes. The differentially expressed genes are notably associated with myelination and autism spectrum disorders. Conclusions: We show that placental ALLO insufficiency is associated with long-term changes in gene expression in the mouse brain in a sex- and region-specific manner. mRNA profiles of 30-day old WT and plKO mice were generated by 3'mRNA sequencing, in triplicate, using Illumina HiSeq 2500.研究目标：本研究旨在以性别和脑区特异性的方式，探究胎盘别孕烯醇酮（allopregnanolone, ALLO）缺失对小鼠大脑转录组的长期影响。 研究方法：我们通过将Akr1c14-floxed小鼠与Cyp19a-Cre小鼠杂交，特异性敲除滋养层细胞中编码ALLO合成酶的基因Akr1c14，构建胎盘ALLO敲除小鼠（plKO小鼠）。采用Illumina HiSeq 2500测序平台，通过3'端mRNA测序对30日龄野生型（wild type, WT）与plKO小鼠的脑区特异性mRNA表达谱进行三次生物学重复检测。 研究结果：RNA测序分析显示，胎盘ALLO缺失与脑区和性别特异性的基因表达变化显著相关。差异表达基因主要与髓鞘形成及孤独症谱系障碍（autism spectrum disorders, ASD）密切关联。 研究结论：本研究证实，胎盘ALLO不足会以性别和脑区特异性的方式，引发小鼠大脑中长期的基因表达改变。本次研究采用Illumina HiSeq 2500测序平台，通过3'端mRNA测序完成了30日龄WT与plKO小鼠的mRNA表达谱构建，实验设置三次生物学重复。