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Mol. Cell. Biol. doi:10.1128/MCB.02041-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Abnormal sympatho-adrenal development and systemic hypotension in PHD3-/- mice

The Henry Wellcome Building for Molecular Physiology, University of Oxford, Headington Campus, Roosevelt Drive, Oxford, OX3 7BN, UK.; School of Biosciences, Cardiff University, Museum Avenue, P.O. Box 911, Cardiff, CF10 3US, UK.; Laboratorio de Investigaciones Biomédicas, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Sevilla, Spain.; The Henry Wellcome Building for Genomic Medicine, University of Oxford, Headington Campus, Roosevelt Drive, Oxford, OX3 7BN, UK.; Department for Transgene Technology and Gene Therapy, VIB, 3000 Leuven, Belgium.; The Center for Transgene Technology and Gene Therapy (CTG), K. U. Leuven, 3000 Leuven, Belgium.; Renal Laboratory, Hammersmith Campus, Imperial College London, Du Cane Road, London, W12 ONN, UK

^* To whom correspondence should be addressed. Email: pjr{at}well.ox.ac.uk.

	Abstract

Cell culture studies have implicated the oxygen-sensitive HIF prolyl hydroxylase PHD3 in the regulation of neuronal apoptosis. To better understand this function in vivo, we have created PHD3-/- mice and analysed the neuronal phenotype. Reduced apoptosis in superior cervical ganglion (SCG) neurons cultured from PHD3-/- 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 PHD3-/- mice with HIF-1+/- and HIF-2a+/- mice demonstrated an interaction with HIF-2, but not HIF-1, supporting the non-redundant involvement of a PHD3-HIF-2 pathway in the regulation of sympatho-adrenal development. Despite the increased number of cells, the sympatho-adrenal system appeared hypofunctional in PHD3-/- mice, with reduced target tissue innervation, adrenal medullary secretory capacity, sympatho-adrenal responses and systemic blood pressure. These observations suggest that the role of PHD3 in sympatho-adrenal 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 signalling by hypoxic, metabolic or other stresses could have important effects on key sympatho-adrenal functions such as blood pressure regulation.