GCN2 is Essential for Oligodendrocyte Development and Myelination in the Brains of Mice Born Deficient in Branched‐Chain α‐Ketoacid Dehydrogenase Kinase (BDK)

Abstract

The eukaryotic initiation factor 2 (eIF2) kinase, GCN2, is critical for surviving branched chain amino acid deficiency during early postnatal life. Mice deleted for both BDK and the gene encoding GCN2 are indistinguishable from littermates at birth but beginning at day 7 stop gaining weight, and then become progressively wasted and neurologically unresponsive until expiring by day 15. To understand the cause of the neurological defect, whole brains from GCN2‐BDK double null mice (GB) were compared to wild‐type and heterozygous littermates at days 11–14 postpartum. At d 11–14, GB brains were much lighter than healthy littermates and were extremely fragile and soft upon dissection. Phosphorylation of eIF2 and mRNA expression of Activating Transcription Factor 4 (ATF4) were significantly increased in BDK null brains but not in GB brains. Messenger RNA levels of asparagine synthetase and C/EBP Homologous Protein (CHOP) were also significantly increased in BDK null brains but not in GB brains. Moreover, in brains from GB mice but not BDK null mice, myelin basic protein (MBP) expression and mRNA expression of MBP and Olig2, a marker of pre‐oligodendrocyes, were all reduced greater than 50%. Finally, gene expression of superoxide dismutase 2 (SOD2) in GB was reduced 40%, suggesting a compromised ability to protect against oxidative stress. These data suggest that GCN2 is critically important for oligodendrocyte development and the onset of myelination under conditions of amino acid stress during early postnatal life.