Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Biol Psychiatry. 2017 Jul 15;82(2):127-138. doi: 10.1016/j.biopsych.2016.12.025. Epub 2016 Dec 30.
Diabetes, obesity, and overweight are prevalent pregnancy complications that predispose offspring to neurodevelopmental disorders, including autism, attention-deficit/hyperactivity disorder, and schizophrenia. Although male individuals are three to four times more likely than female individuals to develop these disorders, the mechanisms driving the sex specificity of disease vulnerability remain unclear. Because defective placental insulin receptor (InsR) signaling is a hallmark of pregnancy metabolic dysfunction, we hypothesized that it may be an important contributor and novel mechanistic link to sex-specific neurodevelopmental changes underlying disease risk.
We used Cre/loxP transgenic mice to conditionally target InsRs in fetally derived placental trophoblasts. Adult offspring were evaluated for effects of placental trophoblast-specific InsR deficiency on stress sensitivity, cognitive function, sensorimotor gating, and prefrontal cortical transcriptional reprogramming. To evaluate molecular mechanisms driving sex-specific outcomes, we assessed genome-wide expression profiles in the placenta and fetal brain.
Male, but not female, mice with placental trophoblast-specific InsR deficiency showed a significantly increased hypothalamic-pituitary-adrenal axis stress response and impaired sensorimotor gating, phenotypic effects that were associated with dysregulated nucleotide metabolic processes in the male prefrontal cortex. Within the placenta, InsR deficiency elicited changes in gene expression, predominantly in male mice, reflecting potential shifts in vasculature, amino acid transport, serotonin homeostasis, and mitochondrial function. These placental disruptions were associated with altered gene expression profiles in the male fetal brain and suggested delayed cortical development.
Together, these data demonstrate the novel role of placental InsRs in sex-specific neurodevelopment and reveal a potential mechanism for neurodevelopmental disorder risk in pregnancies complicated by maternal metabolic disorders, including diabetes and obesity.
糖尿病、肥胖症和超重是常见的妊娠并发症，使后代易患神经发育障碍，包括自闭症、注意缺陷多动障碍和精神分裂症。尽管男性患这些疾病的可能性是女性的三到四倍，但导致疾病易感性性别特异性的机制仍不清楚。由于胎盘胰岛素受体 (InsR) 信号转导缺陷是妊娠代谢功能障碍的标志，我们假设它可能是导致疾病风险相关的性别特异性神经发育变化的重要因素和新的机制联系。
我们使用 Cre/loxP 转基因小鼠对胎儿来源的胎盘滋养细胞中的 InsRs 进行条件性靶向。对成年后代进行评估，以了解胎盘滋养细胞特异性 InsR 缺失对应激敏感性、认知功能、感觉运动门控和前额叶皮质转录重编程的影响。为了评估驱动性别特异性结果的分子机制，我们评估了胎盘和胎儿大脑中的全基因组表达谱。
雄性，而不是雌性，具有胎盘滋养细胞特异性 InsR 缺失的小鼠表现出明显增加的下丘脑-垂体-肾上腺轴应激反应和感觉运动门控受损，这些表型效应与雄性前额叶皮质中核苷酸代谢过程的失调有关。在胎盘内，InsR 缺失引起了基因表达的变化，主要在雄性小鼠中，反映了潜在的血管、氨基酸转运、血清素稳态和线粒体功能的变化。这些胎盘紊乱与雄性胎儿大脑中的基因表达谱改变有关，并提示皮质发育延迟。
这些数据共同证明了胎盘 InsRs 在性别特异性神经发育中的新作用，并揭示了包括糖尿病和肥胖症在内的母体代谢紊乱妊娠中神经发育障碍风险的潜在机制。
