Oxygen levels epigenetically regulate fate switching of neural precursor cells via hypoxia-inducible factor 1α-notch signal interaction in the developing brain.
Oxygen levels in tissues including the embryonic brain are lower than those in the atmosphere. We reported previously that Notch signal activation induces demethylation of astrocytic genes, conferring astrocyte differentiation ability on midgestational neural precursor cells (mgNPCs). Here, we show that the oxygen sensor hypoxia-inducible factor 1α (HIF1α) plays a critical role in astrocytic gene demethylation in mgNPCs by cooperating with the Notch signaling pathway. Expression of constitutively active HIF1α and a hyperoxic environment, respectively, promoted and impeded astrocyte differentiation in the developing brain. Our findings suggest that hypoxia contributes to the appropriate scheduling of mgNPC fate determination.
Laboratory of Molecular Neuroscience, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara, Japan.
Tetsuji
T
Mutoh
Tsukasa
T
Sanosaka
Kei
K
Ito
Kinichi
K
Nakashima
D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D002454:Cell Differentiation; D015687:Cell Hypoxia; D002478:Cells, Cultured; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D053605:Leukemia Inhibitory Factor / Q000502:physiology; D051379:Mice; D008813:Mice, Inbred ICR; D058953:Neural Stem Cells / Q000378:metabolism / Q000502:physiology*; D010100:Oxygen / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction
D005904:Glial Fibrillary Acidic Protein; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D051880:Receptors, Notch; D010100:Oxygen