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Abnormal sympathoadrenal development and systemic hypotension in PHD3-/- mice.
Tammie Bishop1, Denis Gallagher, Alberto Pascual
1The Henry Wellcome Building for Molecular Physiology, University of Oxford, Headington Campus, Roosevelt Drive, Oxford OX3 7BN, United Kingdom.
Molecular and Cellular Biology
|March 12, 2008
Summary
The hypoxia-inducible factor (HIF) prolyl hydroxylase PHD3 is crucial for normal development of the sympathoadrenal system. Loss of PHD3 leads to increased cell numbers but impaired function and lower blood pressure.
Area of Science:
- Neuroscience
- Developmental Biology
- Molecular Biology
Background:
- Cell culture studies suggest PHD3 regulates neuronal apoptosis.
- Hypoxia-inducible factors (HIFs) are key regulators of cellular response to oxygen levels.
Purpose of the Study:
- To investigate the in vivo role of PHD3 in neuronal development and function.
- To elucidate the interaction between PHD3 and HIFs in the sympathoadrenal system.
Main Methods:
- Generation and analysis of PHD3 knockout (PHD3(-/-)) mice.
- Genetic crosses with HIF-1alpha and HIF-2alpha heterozygous mice.
- Assessment of neuronal apoptosis, cell numbers, and sympathoadrenal system function.
Main Results:
- PHD3(-/-) mice exhibit reduced apoptosis and increased cell numbers in the superior cervical ganglion (SCG), adrenal medulla, and carotid body.
- A functional interaction between PHD3 and HIF-2alpha, but not HIF-1alpha, was observed.
- Despite increased cell mass, the sympathoadrenal system in PHD3(-/-) mice was hypofunctional, showing reduced innervation, secretory capacity, and blood pressure.
Conclusions:
- PHD3 is essential for the proper anatomical and physiological development of the sympathoadrenal system, beyond just controlling cell survival.
- A PHD3-HIF-2alpha pathway regulates sympathoadrenal development.
- Dysregulation of PHD3 can impact critical functions like blood pressure regulation.
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