Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, C084

Oral Communications

Hypoxia-inducible Factor 2 alpha is Essential for Proper Brain Development

K. Kleszka1, T. Leu1, S. Pechlivanis2, H. Jastrow3, J. Fandrey1, T. Schreiber1

1. Institute of Physiology, University Hospital Essen, Essen, Germany. 2. IMIBE, University Hospital Essen, Essen, Germany. 3. Imaging Center Essen, University Hospital Essen, Essen, Germany.

Sufficient tissue oxygenation is required for regular function and survival of cells. Especially in the brain, oxygen supply must be tightly regulated to avoid hypoxia (shortage of oxygen) and irreversible cell damage. The transcription factor complex hypoxia-inducible factor (HIF) plays a key role in the adaptation of cells to hypoxia. Particularly, neural stem cells are sensitive to fluctuating oxygen concentrations. To examine the role of the HIF isoform HIF-2α during brain development, mice with a neuronal-specific knockout of HIF-2α were bred. When brains of adult mice were evaluated, a reduction of neurons, especially pyramidal cells, of synapses and of oligodendrocytes in the cortex in HIF-2α knockout mice was observed compared to wild type animals. Loss of pyramidal neurons occurred mainly in the retrosplenial cortex, a brain region that underpins a range of cognitive functions, including memory and navigation. Accordingly, our behavioral studies showed disturbed cognitive abilities in HIF-2α knockout mice, mainly concerning learning aptitude and ability of retrospection. For mechanistic studies, neural stem cells were extracted from postnatal brains and cultivated as neurospheres (3-dimensional cell clusters) in various oxygen conditions (21%, 1% and 0.2% O2). Here, we found that loss of HIF-2α impaired differentiation into neurons and oligodendrocytes, synapse formation and migration as well as prohibiting neural stem cells from death. Genetic analyses confirm that loss in oligodendrocytes is accompanied by diminished Olig2 expression. Furthermore, we hypothesize that up-regulation of NeuroD1 in HIF-2α deficient stem cells leads to a migration deficit to the retrosplenial cortex due to its role in building topographical hierarchies in the developing cortex. This needs to be further evaluated in future. In conclusion, HIF-2α plays a significant role in adequate development of the brain and in adaptation of cells to hypoxia.

Where applicable, experiments conform with Society ethical requirements