Hypoxia during embryogenesis - its physiological role and the effect of anti-hypoxia drugs in neural crest cell development

Neural crest cells are a group of cells transiently seen during early embryogenesis. They arise from dorsal neural tube by epithelial-mesenchymal transition (EMT), acquire motility, migrate and differentiate into peripheral nerves as well as major skeletal components of head and neck structures. EMT is partly analogous to cancer metastasis, sharing the molecular mechanism for cell dissociation. However, it is not clear how EMT in embryos is tightly regulated temporally and spatially, while in cancer it is not.

We recently found that hypoxia, which occurs transiently during development prior to vasculogenesis, promotes emigration of neural crest cells from the head neural tube (Scully et al., 2016). This is reminiscent of the fact that local tissue hypoxia in cancer promotes metastasis. Hypoxic cellular response is exerted by activation of Hypoxia Inducible Factor (HIF)-dependent transcriptional activation, both in adult and embryos. While embryos are naturally hypoxic especially prior to blood circulation, in adults hypoxia is a pathological condition caused by stroke, heart attack or anemia, for example. There has been a much progress in development of pharmaceutical drugs that activate the HIF pathway thus aiming to counteract hypoxic conditions. Our finding that HIF promotes induction of neural crest cells, has raised a possibility that activation of the HIF pathway by such drugs could be a therapeutic strategy for families who suffer from inherited congenital diseases caused by a shortage of neural crest cells. We are currently studying the impact of application of such drugs in embryo development, particularly the development of head structures.

Reference: Scully D, Keane E, Batt E, Karunakaran P, Higgins DF, Itasaki, N. Hypoxia promotes production of neural crest cells in the embryonic head. Development 143, 1742-1752, 2016

Figure 1: Chick embryos with neural crest staining 

2-day-old chick embryos grown in ovo (in the shell) (A), ex ovo (out of the shell, in ambient air) (B) and ex ovo in the presence of dimethyloxaloylglycine that stabilizes HIF protein thus mimicking the hypoxic cellular response (C). Embryos are stained for Sox10 by RNA in situ hybridization to highlight neural crest cells. The embryo grown ex ovo shows reduced neural crest cells (B) compared to the in ovo cultured one (A). Note that Sox10 expression in the otic vesicles (ov) is not reduced. Dimethyloxaloylglycine restores induction of neural crest cells (C).   

Figure 2: Analyses of skeletal development 

11-days-old chick embryo stained for cartilage (blue) and bone (red)

Figure 3: microCT analyses 1  

MicroCT analysis of embryos treated with HIF-promoting drugs by A. Kumar, a student supported by Anatomical Society. The work is in collaboration with T. Davies in Faculty of Science, University of Bristol.

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