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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.

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