Redox Control in Mammalian Embryo Development

The development of an embryo constitutes a complex choreography of regulatory events that underlies precise temporal and spatial control. Throughout this process the embryo encounters ever changing environments, which challenge its metabolism. Oxygen is required for embryogenesis but it also poses a potential hazard via formation of reactive oxygen and reactive nitrogen species (ROS/RNS). These metabolites are capable of modifying macromolecules (lipids, proteins, nucleic acids) and altering their biological functions. On one hand, such modifications may have deleterious consequences and must be counteracted by antioxidant defense systems. On the other hand, ROS/RNS function as essential signal transducers regulating the cellular phenotype. In this context the combined maternal/embryonic redox homeostasis is of major importance and dysregulations in the equilibrium of pro- and antioxidative processes retard embryo development, leading to organ malformation and embryo lethality. Silencing the in vivo expression of pro- and antioxidative enzymes provided deeper insights into the role of the embryonic redox equilibrium. Moreover, novel mechanisms linking the cellular redox homeostasis to gene expression regulation have recently been discovered (oxygen sensing DNA demethylases and protein phosphatases, redox-sensitive microRNAs and transcription factors, moonlighting enzymes of the cellular redox homeostasis) and their contribution to embryo development is critically reviewed. Antioxid. Redox Signal. 13, 833–875. Introduction Mammalian Redox-Homeostasis Pro-oxidative mechanisms Antioxidative defense mechanisms Developmental consequences of redox alterations Redox Control During Embryo Development Normal mouse embryo development Embryonic antioxidative capacity Oxygen requirement and energy metabolism during early embryogenesis ROS-mediated teratogenesis Expression of ROS/RNS producing enzymes during murine embryogenesis Gamete formation, fertilization, and organogenesis Redox control of cellular processes during embryogenesis In Vivo Gene Inactivation Affects Embryonic Redox Homeostasis (Knockout Mice) Knockout of pro-oxidative enzymes Knockout of antioxidative enzymes Redox-Dependent Epigenetic Control of Embryonic Gene Expression Histone acetylation and deacetylation DNA and histone methylation ATP-dependent chromosome remodeling Redox-Dependent Transcriptional Control of Embryonic Gene Expression Nuclear factor κB Activator protein-1 Nrf-ARE system Transcriptional activities of hypoxia inducible factors Redox effector factor-1/apurinic/apyrimidinic endonuclease-1 Redox-Dependent Post-Transcriptional Control Mechanisms of Gene Expression Cytoplasmic polyadenylation and translational masking Iron regulatory elements Small regulatory RNA species (microRNAs) Alternative splicing Grsf1 dependent translational control Nonsense-mediated decay Post-transcriptional regulation of HIF-1α expression Post-transcriptional regulation of thioredoxin expression Post-transcriptional regulation of cyclooxygenase expression Post-transcriptional regulation of antioxidative enzymes Clinical Relevance of Redox Imbalance in Embryo and Fetal Development Redox-dependent teratogenesis Maternal diabetes mellitus Pre-eclampsia Fetal hypoxia Problems and Perspectives