AbstractBackground & AimsMaternal liver exhibits robust adaptations to pregnancy to accommodate the metabolic needs of developing and growing placenta and fetus by largely unknown mechanisms. We found that achaete-scute homolog-like 1 (Ascl1), 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.MethodsTo investigate whether and how Ascl1 plays a pregnancy-dependent role, we deleted the Ascl1 gene specifically in maternal hepatocytes from mid-gestation until term.ResultsAs a result, we identified multiple Ascl1-dependent phenotypes. Maternal livers lacking Ascl1 exhibited aberrant hepatocyte structure, increased hepatocyte proliferation, enlarged hepatocyte size, reduced albumin production, and elevated release of liver enzymes, indicating maternal liver dysfunction. Simultaneously, maternal pancreas and spleen and the placenta displayed 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 exhibited robust activation of insulin-like growth factor 2 expression, which may contribute to the Ascl1-dependent phenotypes widespread in maternal and uteroplacental compartments.ConclusionIn summary, we demonstrate 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 reveal Ascl1 as a novel and critical regulator of the physiology of pregnancy.SynopsisHow the maternal liver adapts to pregnancy remains elusive. We found that maternal liver activates the expression of Ascl1, a gene encoding a proneuronal transcription factor, to coordinate the adaptations of maternal organs and the growth of the placenta, enabling a healthy pregnancy and normal postnatal growth of the offspring.Graphical Abstract
Activation of Proneuronal Transcription Factor Ascl1 in Maternal Liver Ensures a Healthy Pregnancy
