Cell-autonomous and non-cell-autonomous neuroprotective functions of RORα in neurons and astrocytes during hypoxia

Abstract

There is increasing evidence to suggest that the neuronal response to hypoxia is regulated through their interactions with astrocytes. However, the hypoxia-induced molecular mechanisms within astrocytes which influence neuronal death have yet to be characterized. In this study, we investigated the roles of the nuclear receptor RORa (retinoid-related orphan receptor-a) respectively in neurons and astrocytes during hypoxia using cultures and cocultures of neurons and astrocytes obtained from RORa-deficient mice. We found that loss of RORa function in neuronal cultures increases neuronal death after hypoxia, suggesting a cell-autonomous neuroprotective effect of RORa. Moreover, wild-type neurons cocultured with RORa-deficient astrocytes are characterized by a higher death rate after hypoxia than neurons cocultured with wild-type astrocytes, suggesting that RORa also has a non-cell-autonomous action. By using cocultures of neurons and astrocytes of different genotypes, we showed that this neuroprotective effect of RORa in astrocytes is additive to its effect in neurons, and is mediated in part by cell-to-cell interactions between neurons and astrocytes. We also found that RORa is upregulated by hypoxia in both neurons and astrocytes. Furthermore, our data showed that RORa does not alter oxidative mechanisms during hypoxia but regulates hypoxic inducible factor 1a (HIF-1a) expression, a major regulator of hypoxia sensing, in a cell-specific manner. Indeed, the neuroprotective function of RORa in astrocytes correlates with a downregulation of HIF-1 a selectively in these cells. Altogether, our results show that RORa is a key molecular player in hypoxia, protecting neurons through its dual action in neurons and astrocytes. © 2011 the authors.