Hif-2αprogrammes oxygen chemosensitivity in chromaffin cells

Abstract

The study of transcription factors that determine specialised neuronal functions has provided invaluable insights into the physiology of the nervous system. Peripheral chemoreceptors are neuron-like electro-physiologically excitable cells that link the oxygen content of arterial blood to the neuronal control of breathing. In the adult, this oxygen chemosensitivity is exemplified by the Type I cells of the carotid body and recent work has revealed one isoform of the transcription factor HIF, HIF-2α, to have a non-redundant role in the development and function of that organ. Here we show that the activation of HIF-2α, including isolated overexpression alone, is sufficient to induce oxygen chemosensitivity in the otherwise unresponsive adult adrenal medulla. This phenotypic change in the adrenal medulla was associated with retention of extra-adrenal paraganglioma-like tissues that resemble the foetal organ of Zuckerkandl and also manifest oxygen chemosensitivity. Acquisition of chemosensitivity was associated with changes in the adrenal medullary expression of classes of genes that are ordinarily characteristic of the carotid body, including G-protein regulators and atypical subunits of mitochondrial cytochrome oxidase. Overall, the findings suggest that, at least in certain tissues, HIF-2α acts a phenotypic driver for cells that display oxygen chemosensitivity, providing a route to mechanistic understanding.

Carotid Body Function in Tyrosine Hydroxylase Conditional Olfr78 Knockout Mice

“…Next, we studied differences in the mRNA expression levels of a set of genes that are known to be relevant for CB glomus cell function. 2 , 3 , 14 , 28 , 29 These included Epas1 (encoding HIF2α), 3 atypical mitochondrial complex IV (MCIV) subunit isoforms ( Cox4i2, Cox8b , and Higd1C ), pyruvate carboxylase ( Pcx ), regulator of G-protein-signaling 5 ( Rgs5 ), and tyrosine hydroxylase ( Th ), which is expressed in the highly dopaminergic mature glomus cells. Among these genes, Higd1C , which has been suggested to contribute to the characteristically high sensitivity of glomus cell mitochondria to hypoxia, 28 was significantly upregulated in Olfr78-deficient cells ( Figure 1D and E ).…”