Hypoxia-induced hypomyelination in the developing brain is mammalian target of rapamycin-4E-binding protein-1 signaling dependent.

We hypothesized that changes in the expression levels of genes in the mammalian target of rapamycin are involved in the hypoxia-induced growth retardation in the brain including hypomyelination. Microarray and proteomic studies showed a 2.3-fold increase in the expression levels of eukaryotic translation initiation factor 4E-binding protein-1 and a 3-fold decrease in the levels of FK506-binding protein-1 in a neonatal model of hypoxia, indicating a signal transduction impairment through mammalian target of rapamycin (mTOR). Analysis of hypoxic brain showed a marked decrease in the phosphorylation levels of 4E-binding protein-1, suggesting a reduction of mTOR activity. These data suggest that suppression of mTOR may be the mechanism underlying hypoxia-induced hypomyelination observed in the developing brain.