Hypoxic microenvironment within an embryo induces apoptosis and is essential for proper morphological development

Recent studies have suggested the importance of hypoxia-inducible transcription factors in development, yet the questions of whether hypoxia actually exists in a developing embryo in vivo and, if so, what role it plays in development remain unanswered. In this study, we directly demonstrate that regions of hypoxia, most prominently the hindbrain, otic vesicle, and first branchial arch, exist in a gestational day (GD) 11 rat embryo grown in utero. We also show that varying the oxygen environment of an embryo affects its morphological development. Rat embryos which were grown at 45% oxygen from GD 9-11 showed gross morphological abnormalities, including defective cranial neural tube closure, incomplete otic vesicle invagination, and abnormal somite formation and embryo turning. These embryos, in addition, exhibited reduced cell death. On the other hand, embryos which were grown at 5% oxygen during the same period were stunted in overall growth, yet morphologically normal, and displayed prominent areas of apoptosis. In this study, we propose that embryonic development, like tumor development, requires two different but interactive sets of signals. One set exists in the genetic program for development; the other set arises from changes in the microenvironment of the embryo. Therefore, it is the interplay between these two sets of cues that drives normal embryonic development. The requirement for hypoxia to activate apoptotic cell death is but one example of such interactions.