Kalish Brian T, Kim Eunha, Finander Benjamin, Duffy Erin E, Kim Hyunju, Gilman Casey K, Yim Yeong Shin, Tong Lilin, Kaufman Randal J, Griffith Eric C, Choi Gloria B, Greenberg Michael E, Huh Jun R
Department of Neurobiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.
Nat Neurosci. 2021 Feb;24(2):204-213. doi: 10.1038/s41593-020-00762-9. Epub 2020 Dec 23.
Maternal infection and inflammation during pregnancy are associated with neurodevelopmental disorders in offspring, but little is understood about the molecular mechanisms underlying this epidemiologic phenomenon. Here, we leveraged single-cell RNA sequencing to profile transcriptional changes in the mouse fetal brain in response to maternal immune activation (MIA) and identified perturbations in cellular pathways associated with mRNA translation, ribosome biogenesis and stress signaling. We found that MIA activates the integrated stress response (ISR) in male, but not female, MIA offspring in an interleukin-17a-dependent manner, which reduced global mRNA translation and altered nascent proteome synthesis. Moreover, blockade of ISR activation prevented the behavioral abnormalities as well as increased cortical neural activity in MIA male offspring. Our data suggest that sex-specific activation of the ISR leads to maternal inflammation-associated neurodevelopmental disorders.
孕期母体感染和炎症与后代神经发育障碍有关,但对于这一流行病学现象背后的分子机制却知之甚少。在此,我们利用单细胞RNA测序来分析小鼠胎儿大脑对母体免疫激活(MIA)的转录变化,并确定了与mRNA翻译、核糖体生物合成和应激信号相关的细胞途径中的扰动。我们发现,MIA以白细胞介素-17a依赖的方式激活雄性而非雌性MIA后代的综合应激反应(ISR),这降低了整体mRNA翻译并改变了新生蛋白质组的合成。此外,阻断ISR激活可预防MIA雄性后代的行为异常以及增加皮质神经活动。我们的数据表明,ISR的性别特异性激活导致了与母体炎症相关的神经发育障碍。