PUBLICATION

Hypoxia Disruption of Vertebrate CNS Pathfinding through EphrinB2 Is Rescued by Magnesium

Authors
Stevenson, T.J., Trinh, T., Kogelschatz, C., Fujimoto, E., Lush, M.E., Piotrowski, T., Brimley, C.J., and Bonkowsky, J.L.
ID
ZDB-PUB-120419-3
Date
2012
Source
PLoS Genetics   8(4): e1002638 (Journal)
Registered Authors
Bonkowsky, Joshua, Fujimoto, Esther, Lush, Mark E., Piotrowski, Tatjana
Keywords
Hypoxia, Embryos, Axons, Magnesium, Axon guidance, Neurons, Zebrafish, Central nervous system
MeSH Terms
  • Ephrin-B2/genetics*
  • Ephrin-B2/metabolism
  • Gene Expression Regulation, Developmental
  • Hypoxia*/metabolism
  • Hypoxia*/pathology
  • Receptor, EphA4/genetics
  • Receptor, EphA4/metabolism
  • Magnesium Sulfate/pharmacology*
  • Animals, Genetically Modified
  • Signal Transduction
  • Axons/metabolism
  • Axons/physiology
  • Hypoxia-Inducible Factor 1, alpha Subunit*/genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit*/metabolism
  • Animals
  • Central Nervous System/metabolism
  • Neurons/metabolism*
  • Neurons/pathology
  • Transcriptional Activation
  • Gene Knockdown Techniques
  • Zebrafish*/genetics
  • Zebrafish*/physiology
  • Neuroprotective Agents/pharmacology*
(all 23)
PubMed
22511881 Full text @ PLoS Genet.
Abstract

The mechanisms of hypoxic injury to the developing human brain are poorly understood, despite being a major cause of chronic neurodevelopmental impairments. Recent work in the invertebrate Caenorhabditis elegans has shown that hypoxia causes discrete axon pathfinding errors in certain interneurons and motorneurons. However, it is unknown whether developmental hypoxia would have similar effects in a vertebrate nervous system. We have found that developmental hypoxic injury disrupts pathfinding of forebrain neurons in zebrafish (Danio rerio), leading to errors in which commissural axons fail to cross the midline. The pathfinding defects result from activation of the hypoxia-inducible transcription factor (hif1) pathway and are mimicked by chemical inducers of the hif1 pathway or by expression of constitutively active hif1α. Further, we found that blocking transcriptional activation by hif1α helped prevent the guidance defects. We identified ephrinB2a as a target of hif1 pathway activation, showed that knock-down of ephrinB2a rescued the guidance errors, and showed that the receptor ephA4a is expressed in a pattern complementary to the misrouting axons. By targeting a constitutively active form of ephrinB2a to specific neurons, we found that ephrinB2a mediates the pathfinding errors via a reverse-signaling mechanism. Finally, magnesium sulfate, used to improve neurodevelopmental outcomes in preterm births, protects against pathfinding errors by preventing upregulation of ephrinB2a. These results demonstrate that evolutionarily conserved genetic pathways regulate connectivity changes in the CNS in response to hypoxia, and they support a potential neuroprotective role for magnesium.

Genes / Markers
Figures
Figure Gallery (7 images)
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Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
psi1TgTransgenic Insertion
    zc57TgTransgenic Insertion
      zc69TgTransgenic Insertion
        zc72TgTransgenic Insertion
          zc73TgTransgenic Insertion
            zc74TgTransgenic Insertion
              zc75TgTransgenic Insertion
                zc76TgTransgenic Insertion
                  1 - 8 of 8
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                  Human Disease / Model
                  No data available
                  Sequence Targeting Reagents
                  Target Reagent Reagent Type
                  efnb2aMO1-efnb2aMRPHLNO
                  1 - 1 of 1
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                  Fish
                  Antibodies
                  No data available
                  Orthology
                  No data available
                  Engineered Foreign Genes
                  Marker Marker Type Name
                  EGFPEFGEGFP
                  GAL4EFGGAL4
                  GFPEFGGFP
                  TagRFPEFGTagRFP
                  1 - 4 of 4
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                  Mapping
                  No data available