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PMID:17215402

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Citation

Milosevic, J, Maisel, M, Wegner, F, Leuchtenberger, J, Wenger, RH, Gerlach, M, Storch, A and Schwarz, J (2007) Lack of hypoxia-inducible factor-1 alpha impairs midbrain neural precursor cells involving vascular endothelial growth factor signaling. J. Neurosci. 27:412-21

Abstract

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.

Links

PubMed Online version:10.1523/JNEUROSCI.2482-06.2007

Keywords

Animals; Cell Differentiation/physiology; Cell Survival/physiology; Dopamine/physiology; Humans; Hypoxia-Inducible Factor 1, alpha Subunit/deficiency; Hypoxia-Inducible Factor 1, alpha Subunit/genetics; Hypoxia-Inducible Factor 1, alpha Subunit/physiology; Mesencephalon/cytology; Mesencephalon/physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Neurons/metabolism; Neurons/pathology; Signal Transduction/physiology; Stem Cells/metabolism; Stem Cells/pathology; Substantia Nigra/cytology; Substantia Nigra/physiology; Vascular Endothelial Growth Factor A/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:VEGFA

acts_upstream_of_or_within

GO:0071542: dopaminergic neuron differentiation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:106918

P

  • results_in_acquisition_of_features_of:(CL:0000700)

Seeded From UniProt

complete

MOUSE:HIF1A

acts_upstream_of_or_within

GO:0071542: dopaminergic neuron differentiation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:103178

P

  • results_in_acquisition_of_features_of:(CL:0000700)

Seeded From UniProt

complete

MOUSE:HIF1A

acts_upstream_of_or_within

GO:0002052: positive regulation of neuroblast proliferation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:103178

P

Seeded From UniProt

complete

MOUSE:HIF1A

acts_upstream_of_or_within

GO:0071542: dopaminergic neuron differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2386679

P

  • occurs_in:(EMAPA:16974)
  • results_in_acquisition_of_features_of:(CL:0000700)

Seeded From UniProt

complete

MOUSE:HIF1A

acts_upstream_of_or_within

GO:0071542: dopaminergic neuron differentiation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:103178

P

results_in_acquisition_of_features_of:(CL:0000700)

Seeded From UniProt

complete

MOUSE:VEGFA

acts_upstream_of_or_within

GO:0002052: positive regulation of neuroblast proliferation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:106918

P

Seeded From UniProt

complete

MOUSE:VEGFA

acts_upstream_of_or_within

GO:0071542: dopaminergic neuron differentiation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:106918

P

results_in_acquisition_of_features_of:(CL:0000700)

Seeded From UniProt

complete


See also

References

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