Abnormal sympathoadrenal development and systemic hypotension in PHD3-/- mice.
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.
Bishop
Tammie
T
The Henry Wellcome Building for Molecular Physiology, University of Oxford, Headington Campus, Roosevelt Drive, Oxford OX3 7BN, United Kingdom.
Gallagher
Denis
D
Pascual
Alberto
A
Lygate
Craig A
CA
de Bono
Joseph P
JP
Nicholls
Lynn G
LG
Ortega-Saenz
Patricia
P
Oster
Henrik
H
Wijeyekoon
Bhathiya
B
Sutherland
Andrew I
AI
Grosfeld
Alexandra
A
Aragones
Julian
J
Schneider
Martin
M
van Geyte
Katie
K
Teixeira
Dania
D
Diez-Juan
Antonio
A
Lopez-Barneo
Jose
J
Channon
Keith M
KM
Maxwell
Patrick H
PH
Pugh
Christopher W
CW
Davies
Alun M
AM
Carmeliet
Peter
P
Ratcliffe
Peter J
PJ
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
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