Decoding the Role of Oxygen Levels in Regulating Mammalian Embryogenesis

Oxygen is traditionally regarded as a permissive physiological factor, yet my recent work, alongside a few other studies, reveal an opposing perspective: dynamic changes in oxygen levels play pivotal roles in mammalian embryogenesis. Clinical studies indicate that embryos in late gestation become increasingly dependent on high oxygen levels, with gestational hypoxia contributing to approximately 20% of embryonic lethality. In contrast, my work shows that early stages mammalian embryos require hypoxia for proper timing of lineage fate decision. My work suggests that oxygen regulates mammalian embryo development in stage- and tissue-specific way, yet the mechanisms behind remained unclear. This proposal integrates my newly optimised embryological methods, my longstanding background in early mammalian embryo development, and the outstanding research environment at the Gurdon Institute and Department of Genetics, University of Cambridge, to investigate three complementary questions: 1) What drives tissue-specific responsiveness to hypoxia in early development? 2) What mechanisms enable early embryonic tissues to recover from hypoxia exposure? 3) What causes the loss of hypoxia tolerance as development progresses? Together, these studies aim to reveal fundamental principles governing oxygen-regulated developmental timing and tissue plasticity, with the long-term goal of informing strategies to treat congenital defects caused by gestational hypoxia.