Dear Colleagues,

Stress is any stimulus that diminishes embryonic or fetal growth or diminishes differentiated function per cell during prenatal development. Stress signaling is mediated by pathways that sense and proportionally respond to stress in the moment and integrate responses in the moment in such a way as to anticipate stress-diminished outcomes that are cumulative over longer periods of stress. In particular, of the 500 protein kinases shared by the mouse and human kinome, a small set routinely respond to stress, but not mitogenic stimuli. These kinases integrate immediate proportional stress responses in the moment with longer-term cellular and developmental homeostatic outcomes. Substrates of protein kinases are manifold and throughout all cellular compartments, but some of the most important ones are developmental regulators of nuclear transcription factors that regulate stemness and the multiple differentiated lineages that may arise after stemness is lost. Stress is most significant when it depletes energy and perturbs stemness and differentiation balance to create miscarriage or teratogenic effects, but an important area of concern are lower exposures that create epigenetic memory that affect prenatal embryonic and placental development but can persist and affect postnatal health.

High-risk periods of stress effects on embryonic development occur when differentiated lineages are set aside and proliferation remains high, making cells sensitive to energy-consuming stress responses at a time when stem cells are in an anaerobic glycolytic metabolism that enables rapid proliferation based on sparing carbon from oxidation in the nucleus, but at the expense of low ATP production/glucose molecule.

In this Special Issue of Cells, we invite your contributions, either in the form of original research articles, reviews, or shorter perspective articles on all aspects related to the theme of “Stress Signaling during High-Risk Periods of Embryonic Development”. Articles with mechanistic and functional insights from a cell and molecular biological perspective are especially welcome. Relevant topics include but are not limited to;

• Novel and seminal means to test for mechanisms and signaling during high-risk periods;
• Reviews on novel and seminal insights of teratogenic and epigenetic signaling during high-risk periods
• Epidemiologic or other original mechanistic data that support or refute the hypothesis that mechanistic stresses that activate inflammatory or reactive oxidative stress mechanisms synergize negatively to compound the negative effects of maternal stress hormones or lack of maternal satiety hormones;
• How to use animal or in vitro cellular models to complement each other in establishing stress response mechanisms or deleterious stress exposures but also contribute to risk analysis of real-world impacts;
• Novel and seminal data that identify protein kinases and their substrates that mediate important parts of stress responses that can at first be adaptive but may become maladaptive with prolonged exposure;
• Bulk or single-cell transcriptomic, methylomic, or proteomic data that help to identify normal and stress-induced mechanisms on the scale of large program changes, compared with normal development.

Dr. Daniel Rappolee
Guest Editor

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• stress
• protein kinases
• transcription factors
• teratogenesis
• miscarriage
• recurrent pregnancy loss
• implantation failure
• epigenetic
• transcriptomic
• proliferation
• stemness
• anabolism (warburg anabolism)
• placental trophoblast stem cells (TSC)
• embryonic stem cells (ESC)
• extraembryonic endoderm (XEN, ExEndo)
• mammalian development