Activation of Proneuronal Transcription Factor Ascl1 in Maternal Liver Ensures a Healthy Pregnancy.
Activation of Proneuronal Transcription Factor Ascl1 in Maternal Liver Ensures a Healthy Pregnancy.
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DOI：
10.1016/j.jcmgh.2021.08.009
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发表时间：
2022
影响因子：
7.2
通讯作者：
Dai G
中科院分区：
文献类型：
--
作者：
Lee J;Garcia V;Nambiar SM;Jiang H;Dai G
母体肝脏对妊娠表现出强大的适应性，以适应发育中和生长中的胎盘和胎儿的代谢需求，其机制基本未知。我们发现Ascl1是一种编码神经元发育所必需的基本螺旋-环-螺旋转录因子的基因，在小鼠妊娠后半期的母体肝细胞中高度激活。为了研究Ascl1是否以及如何发挥妊娠依赖的作用，我们删除了从中期到足月的母体肝细胞中特异的Ascl1基因。结果，我们鉴定了多种Ascl1依赖的表型。缺乏Ascl1的母肝表现为肝细胞结构异常，肝细胞增殖增加，肝细胞体积增大，白蛋白生成减少，肝酶释放增加，提示母肝功能障碍。同时，母体胰腺、脾和胎盘显示出明显的过度生长；母体盲肠微生物群的几个细菌亚群的相对丰度发生了变化。此外，母体肝脏Ascl1缺乏的母鼠在断奶后出生的小鼠出现了异常的出生后发育，这意味着不良的妊娠结局。从机制上讲，我们发现Ascl1缺乏的母体肝细胞表现出胰岛素样生长因子2表达的强烈激活，这可能是广泛存在于母体和子宫胎盘室的Ascl1依赖表型的原因。综上所述，我们发现母体肝脏通过激活Ascl1的表达，调节母体器官的适应和胎盘的生长，以维持健康的妊娠。我们的研究表明，Ascl1是一种新的和关键的妊娠生理调节因子。
Maternal liver shows robust adaptations to pregnancy to accommodate the metabolic needs of the developing and growing placenta and fetus by largely unknown mechanisms. We found that Ascl1, a gene encoding a basic helix-loop-helix transcription factor essential for neuronal development, is highly activated in maternal hepatocytes during the second half of gestation in mice. To investigate whether and how Ascl1 plays a pregnancy-dependent role, we deleted the Ascl1 gene specifically in maternal hepatocytes from midgestation until term. As a result, we identified multiple Ascl1-dependent phenotypes. Maternal livers lacking Ascl1 showed aberrant hepatocyte structure, increased hepatocyte proliferation, enlarged hepatocyte size, reduced albumin production, and increased release of liver enzymes, indicating maternal liver dysfunction. Simultaneously, maternal pancreas and spleen and the placenta showed marked overgrowth; and the maternal ceca microbiome showed alterations in relative abundance of several bacterial subpopulations. Moreover, litters born from maternal hepatic Ascl1-deficient dams experienced abnormal postnatal growth after weaning, implying an adverse pregnancy outcome. Mechanistically, we found that maternal hepatocytes deficient for Ascl1 showed robust activation of insulin-like growth factor 2 expression, which may contribute to the Ascl1-dependent phenotypes widespread in maternal and uteroplacental compartments. In summary, we show that maternal liver, via activating Ascl1 expression, modulates the adaptations of maternal organs and the growth of the placenta to maintain a healthy pregnancy. Our studies show that Ascl1 is a novel and critical regulator of the physiology of pregnancy.
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