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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-1265

Milosevic, J; Maisel, M; Wegner, F; Leuchtenberger, J; Wenger, R H; Gerlach, M; Storch, A; Schwarz, J (2007). Lack of hypoxia-inducible factor-1 alpha impairs midbrain neural precursor cells involving vascular endothelial growth factor signaling. Journal of Neuroscience, 27(2):412-421.


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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-1alpha (HIF-1alpha) 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-1alpha conditional knock-out (HIF-1alpha CKO) mNPCs showed midbrain-specific impairment of survival and proliferation. Dopaminergic differentiation of HIF-1alpha CKO mNPCs in vitro was markedly reduced. Expression of vascular endothelial growth factor (VEGF) mRNA was reduced in HIF-1alpha CKO mNPCs, whereas erythropoietin signaling was not affected. Treatment of HIF-1alpha CKO mNPCs with 50 ng/ml VEGF partially recovered proliferation and dopaminergic differentiation in vitro. In substantia nigra (SN) of adult HIF-1alpha 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-1alpha 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-1alpha seems to be a transcription factor relevant to the development and survival of substantia nigra dopaminergic neurons involving VEGF signaling.




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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
DDC:570 Life sciences; biology
Deposited On:11 Feb 2008 12:22
Last Modified:27 Nov 2013 17:18
Publisher:Society for Neuroscience
Additional Information:Holder of copyright: The Society for Neuroscience
Publisher DOI:10.1523/JNEUROSCI.2482-06.2007
PubMed ID:17215402

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