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<jats:title>ABSTRACT</jats:title> <jats:p>Cell culture studies have implicated the oxygen-sensitive hypoxia-inducible factor (HIF) prolyl hydroxylase PHD3 in the regulation of neuronal apoptosis. To better understand this function in vivo, we have created <jats:italic>PHD3</jats:italic> <jats:sup> <jats:italic>−</jats:italic>/<jats:italic>−</jats:italic> </jats:sup> mice and analyzed the neuronal phenotype. Reduced apoptosis in superior cervical ganglion (SCG) neurons cultured from <jats:italic>PHD3</jats:italic> <jats:sup> <jats:italic>−</jats:italic>/<jats:italic>−</jats:italic> </jats:sup> mice is associated with an increase in the number of cells in the SCG, as well as in the adrenal medulla and carotid body. Genetic analysis by intercrossing <jats:italic>PHD3</jats:italic> <jats:sup> <jats:italic>−</jats:italic>/<jats:italic>−</jats:italic> </jats:sup> mice with <jats:italic>HIF-1a</jats:italic> <jats:sup> <jats:italic>+</jats:italic>/<jats:italic>−</jats:italic> </jats:sup> and <jats:italic>HIF-2a</jats:italic> <jats:sup> <jats:italic>+</jats:italic>/<jats:italic>−</jats:italic> </jats:sup> mice demonstrated an interaction with HIF-2α but not HIF-1α, supporting the nonredundant involvement of a PHD3-HIF-2α pathway in the regulation of sympathoadrenal development. Despite the increased number of cells, the sympathoadrenal system appeared hypofunctional in <jats:italic>PHD3</jats:italic> <jats:sup> <jats:italic>−</jats:italic>/<jats:italic>−</jats:italic> </jats:sup> mice, with reduced target tissue innervation, adrenal medullary secretory capacity, sympathoadrenal responses, and systemic blood pressure. These observations suggest that the role of PHD3 in sympathoadrenal development extends beyond simple control of cell survival and organ mass, with functional PHD3 being required for proper anatomical and physiological integrity of the system. Perturbation of this interface between developmental and adaptive signaling by hypoxic, metabolic, or other stresses could have important effects on key sympathoadrenal functions, such as blood pressure regulation.</jats:p>

Original publication

DOI

10.1128/mcb.02041-07

Type

Journal article

Journal

Molecular and Cellular Biology

Publisher

American Society for Microbiology

Publication Date

15/05/2008

Volume

28

Pages

3386 - 3400