Chen E Y, Fujinaga M, Giaccia A J
Mayer Cancer Biology Research Laboratory, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California 94305-5468, USA.
Teratology. 1999 Oct;60(4):215-25. doi: 10.1002/(SICI)1096-9926(199910)60:4<215::AID-TERA6>3.0.CO;2-2.
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.
近期研究表明缺氧诱导转录因子在发育过程中具有重要性，然而，在发育中的胚胎体内是否实际存在缺氧情况，以及如果存在，它在发育中发挥何种作用等问题仍未得到解答。在本研究中，我们直接证明了在子宫内生长的妊娠第11天（GD11）大鼠胚胎中存在缺氧区域，最显著的是后脑、耳泡和第一鳃弓。我们还表明，改变胚胎的氧气环境会影响其形态发育。从GD9至11在45%氧气浓度下生长的大鼠胚胎表现出明显的形态异常，包括颅骨神经管闭合缺陷、耳泡内陷不完全、体节形成异常和胚胎旋转异常。此外，这些胚胎的细胞死亡减少。另一方面，同期在5%氧气浓度下生长的胚胎整体生长发育迟缓，但形态正常，并显示出明显的细胞凋亡区域。在本研究中，我们提出胚胎发育与肿瘤发育一样，需要两组不同但相互作用的信号。一组存在于发育的遗传程序中；另一组则源于胚胎微环境的变化。因此，正是这两组信号之间的相互作用驱动着正常的胚胎发育。缺氧激活凋亡性细胞死亡的需求只是这种相互作用的一个例子。
