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Preferential activation of HIF-2α adaptive signalling in neuronal-like cells in response to acute hypoxia

Mart�n-Arag�n Baudel, Miguel A. S.; Rae, Mick T.; Darlison, Mark G.; Poole, Amy V.; Fraser, Jennifer A.


Miguel A. S. Mart�n-Arag�n Baudel

Mark G. Darlison

Jennifer A. Fraser


George Simos


Stroke causes severe neuronal damage as disrupted cerebral blood flow starves neurons of oxygen and glucose. The hypoxia inducible factors (HIF-1α and HIF-2α) orchestrate oxygen homeostasis and regulate specific aspects of hypoxic adaptation. Here we show the importance of HIF-2α dependant signalling in neuronal adaptation to hypoxic insult. PC12 and NT2 cells were differentiated into neuronal-like cells using NGF and retinoic acid, and exposed to acute hypoxia (1% O2). Gene and protein expression was analysed by qPCR and immunoblotting and the neuronal-like phenotype was examined. PC12 and NT2 differentiation promoted neurite extension and expression of neuronal markers, NSE and KCC2. Induction of HIF-1α mRNA or protein was not detected in hypoxic neuronal-like cells, however marked induction of HIF-2α mRNA and protein expression was observed. Induction of HIF-1α target genes was also not detected in response to acute hypoxia, however significant induction of HIF-2α transcriptional targets was clearly evident. Furthermore, hypoxic insult dramatically reduced both neurite number and length, and attenuated expression of neuronal markers, NSE and KCC2. This correlated with an increase in expression of the neural progenitor and stem cell-like markers, CD44 and vimentin, suggesting HIF-2α molecular mechanisms could potentially promote regression of neuronal-like cells to a stem-like state and trigger neuronal recovery following ischaemic insult. Our findings suggest the HIF-2α pathway predominates over HIF-1α signalling in neuronal-like cells following acute hypoxia.


Martín-Aragón Baudel, M. A. S., Rae, M. T., Darlison, M. G., Poole, A. V., & Fraser, J. A. (2017). Preferential activation of HIF-2α adaptive signalling in neuronal-like cells in response to acute hypoxia. PLOS ONE, 12(10), Article e0185664.

Journal Article Type Article
Acceptance Date Sep 22, 2017
Online Publication Date Oct 2, 2017
Publication Date Oct 2, 2017
Deposit Date Sep 27, 2017
Publicly Available Date Oct 3, 2017
Journal PLoS ONE
Print ISSN 1932-6203
Publisher Public Library of Science
Peer Reviewed Peer Reviewed
Volume 12
Issue 10
Article Number e0185664
Keywords Stroke, acute hypoxia, neuronal adaptation,
Public URL
Contract Date Oct 3, 2017


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Copyright Statement
© 2017 Martín-Aragón Baudel et al. This is an open access article distributed under the terms of the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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