Extensive research in the field of stem cells and developmental biology has revealed evidence of the role of hypoxia as an important factor regulating self-renewal and differentiation. However, comprehensive information about the exact hypoxia-mediated regulatory mechanism of stem cell fate during early embryonic development is still missing. Using a model of embryoid bodies (EBs) derived from murine embryonic stem cells (ESC), we here tried to encrypt the role of hypoxia-inducible factor 1α(HIF1α) in neural fate during spontaneous differentiation. EBs derived from ESC with the ablated gene for HIF1αhad abnormally increased neuronal characteristics during differentiation. An increased neural phenotype inHif1α-/-EBs was accompanied by the disruption ofβ-catenin signaling together with the increased cytoplasmic degradation ofβ-catenin. The knock-in ofHif1α, as well asβ-catenin ectopic overexpression inHif1α-/-EBs, induced a reduction in neural markers to the levels observed in wild-type EBs. Interestingly, direct interaction between HIF1αandβ-catenin was demonstrated by immunoprecipitation analysis of the nuclear fraction of wild-type EBs. Together, these results emphasize the regulatory role of HIF1αinβ-catenin stabilization during spontaneous differentiation, which seems to be a crucial mechanism for the natural inhibition of premature neural differentiation.

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