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The study of transcription factors that determine specialized neuronal functions has provided invaluable insights into the physiology of the nervous system. Peripheral chemoreceptors are neurone-like electrophysiologically excitable cells that link the oxygen concentration of arterial blood to the neuronal control of breathing. In the adult, this oxygen chemosensitivity is exemplified by type I cells of the carotid body, and recent work has revealed one isoform of the hypoxia- inducible transcription factor (HIF), HIF-2[alpha], as having a nonredundant role in the development and function of that organ. Here, we show that activation of HIF-2[alpha], including isolated overexpression of HIF-2[alpha] but not HIF-1[alpha], is sufficient to induce oxygen chemosensitivity in adult adrenal medulla. This phenotypic change in the adrenal medulla was associated with retention of extra-adrenal paraganglioma-like tissues resembling the fetal organ of Zuckerkandl, which also manifests oxygen chemosensitivity. Acquisition of chemosensitivity was associated with changes in the adrenal medullary expression of gene classes 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-2[alpha] acts as a phenotypic driver for cells that display oxygen chemosensitivity, thus linking 2 major oxygen-sensing systems., Introduction One of the most vital, but still incompletely understood, functions in homeostatic physiology is that of the arterial chemoreceptors that control breathing in response to changes in blood oxygen, [...]

Hypoxia-inducible factor (HIF) is strikingly upregulated in many types of cancer, and there is great interest in applying inhibitors of HIF as anticancer therapeutics. The most advanced of these are small molecules that target the HIF-2 isoform through binding the PAS-B domain of HIF-2[alpha]. These molecules are undergoing clinical trials with promising results in renal and other cancers where HIF-2 is considered to be driving growth. Nevertheless, a central question remains as to whether such inhibitors affect physiological responses to hypoxia at relevant doses. Here, we show that pharmacological HIF-2[alpha] inhibition with PT2385, at doses similar to those reported to inhibit tumor growth, rapidly impaired ventilatory responses to hypoxia, abrogating both ventilatory acclimatization and carotid body cell proliferative responses to sustained hypoxia. Mice carrying a HIF-2[alpha] PAS-B S305M mutation that disrupts PT2385 binding, but not dimerization with HIF-1[beta], did not respond to PT2385, indicating that these effects are on-target. Furthermore, the finding of a hypomorphic ventilatory phenotype in untreated HIF-2[alpha] S305M mutant mice suggests a function for the HIF-2[alpha] PAS-B domain beyond heterodimerization with HIF-1[beta]. Although PT2385 was well tolerated, the findings indicate the need for caution in patients who are dependent on hypoxic ventilatory drive., Introduction Hypoxia-inducible factors (HIFs) are transcriptional factors that mediate a wide range of adaptive responses to low oxygen and play a central role in the maintenance of oxygen homeostasis (reviewed [...]