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The Journal of Neuroscience, January 10, 2007, 27(2):412-421; doi:10.1523/JNEUROSCI.2482-06.2007

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Development/Plasticity/Repair
Lack of Hypoxia-Inducible Factor-1 Impairs Midbrain Neural Precursor Cells Involving Vascular Endothelial Growth Factor Signaling

Javorina Milosevic,¹ Martina Maisel,² Florian Wegner,¹ Julia Leuchtenberger,¹ Roland H. Wenger,³ Manfred Gerlach,⁴ Alexander Storch,² and Johannes Schwarz¹

¹Department of Neurology, University of Leipzig, 04103 Leipzig, Germany, ²Department of Neurology, Technical University of Dresden, 01307 Dresden, Germany, ³Institute of Physiology, University of Zürich, 8057 Zürich, Switzerland, and ⁴Clinical Neurochemistry, Department of Child and Youth Psychiatry and Psychotherapy, University of Würzburg, 97080 Würzburg, Germany

Correspondence should be addressed to Dr. Javorina Milosevic, Department of Neurology, Max-Bürger-Forschungszentrum, Johannisallee 30, 04103 Leipzig, Germany. Email: javorina.milosevic{at}medizin.uni-leipzig.de

Oxygen tension is critical for proliferation of human and murine midbrain-derived neural precursor cells (mNPCs). Here, we conditionally inactivated the hypoxia-responsive transcription factor hypoxia-inducible factor-1 (HIF-1) in murine NPCs to determine its role in proliferation, survival, and dopaminergic differentiation in vitro as well as survival of murine dopaminergic neurons in vivo. HIF-1 conditional knock-out (HIF-1 CKO) mNPCs showed midbrain-specific impairment of survival and proliferation. Dopaminergic differentiation of HIF-1 CKO mNPCs in vitro was markedly reduced. Expression of vascular endothelial growth factor (VEGF) mRNA was reduced in HIF-1 CKO mNPCs, whereas erythropoietin signaling was not affected. Treatment of HIF-1 CKO mNPCs with 50 ng/ml VEGF partially recovered proliferation and dopaminergic differentiation in vitro. In substantia nigra (SN) of adult HIF-1 CKO mice, protein levels of dopaminergic marker molecules such as tyrosine hydroxylase (TH) and aldehyde dehydrogenase were reduced by 41 and 61%, respectively. The cell survival marker Bcl-2 was reduced by 58% while caspase-3 was activated. Nonbiased stereological cell counts of TH-positive neurons in SN of young adult HIF-1 CKO mice revealed a reduction of 31% compared with cre/wt mice (in which the wild- type Hif1a allele is expressed in parallel with the Cre recombinase allele). However, we found no impairment of striatal dopamine concentrations or locomotor behavior. In conclusion, HIF-1 seems to be a transcription factor relevant to the development and survival of substantia nigra dopaminergic neurons involving VEGF signaling.

Key words: neural precursor cells; hypoxia; HIF-1; midbrain; dopaminergic development; apoptosis; VEGF

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Received June 13, 2006; revised Dec. 4, 2006; accepted Dec. 5, 2006.

Correspondence should be addressed to Dr. Javorina Milosevic, Department of Neurology, Max-Bürger-Forschungszentrum, Johannisallee 30, 04103 Leipzig, Germany. Email: javorina.milosevic{at}medizin.uni-leipzig.de

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