title: Abnormal sympathoadrenal development and systemic hypotension in PHD3-/- mice.
abstract: 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 PHD3(-/-) mice and analyzed 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-1a(+/-) and HIF-2a(+/-) mice demonstrated an interaction with HIF-2alpha but not HIF-1alpha, supporting the nonredundant involvement of a PHD3-HIF-2alpha pathway in the regulation of sympathoadrenal development. Despite the increased number of cells, the sympathoadrenal system appeared hypofunctional in PHD3(-/-) 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.
authors.affiliation: The Henry Wellcome Building for Molecular Physiology, University of Oxford, Headington Campus, Roosevelt Drive, Oxford OX3 7BN, United Kingdom.
authors.forename: Tammie
authors.initials: T
authors.lastname: Bishop
authors.forename: Denis
authors.initials: D
authors.lastname: Gallagher
authors.forename: Alberto
authors.initials: A
authors.lastname: Pascual
authors.forename: Craig A
authors.initials: CA
authors.lastname: Lygate
authors.forename: Joseph P
authors.initials: JP
authors.lastname: de Bono
authors.forename: Lynn G
authors.initials: LG
authors.lastname: Nicholls
authors.forename: Patricia
authors.initials: P
authors.lastname: Ortega-Saenz
authors.forename: Henrik
authors.initials: H
authors.lastname: Oster
authors.forename: Bhathiya
authors.initials: B
authors.lastname: Wijeyekoon
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Sutherland
authors.forename: Alexandra
authors.initials: A
authors.lastname: Grosfeld
authors.forename: Julian
authors.initials: J
authors.lastname: Aragones
authors.forename: Martin
authors.initials: M
authors.lastname: Schneider
authors.forename: Katie
authors.initials: K
authors.lastname: van Geyte
authors.forename: Dania
authors.initials: D
authors.lastname: Teixeira
authors.forename: Antonio
authors.initials: A
authors.lastname: Diez-Juan
authors.forename: Jose
authors.initials: J
authors.lastname: Lopez-Barneo
authors.forename: Keith M
authors.initials: KM
authors.lastname: Channon
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Maxwell
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Pugh
authors.forename: Alun M
authors.initials: AM
authors.lastname: Davies
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ratcliffe
mesh_terms: D000222:Adaptation, Physiological; D000311:Adrenal Glands / Q000002:abnormalities* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D005260:Female; D018390:Gene Targeting; D007022:Hypotension / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy; D011393:Procollagen-Proline Dioxygenase / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D017783:Superior Cervical Ganglion / Q000002:abnormalities / Q000473:pathology / Q000503:physiopathology; D013564:Sympathetic Nervous System / Q000002:abnormalities* / Q000473:pathology / Q000503:physiopathology; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D017931:DNA Primers; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011393:Procollagen-Proline Dioxygenase; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C522722:PHD3 protein, mouse