Neuroprotective proteins expressed in the fetus play a critical role during early embryonic neurodevelopment, especially during maternal exposure to alcohol and drugs that cause stress, glutamate neuroexcitotoxicity, and damage to the fetal brain, if prolonged. We have identified a novel protein, carboxypeptidase E-¿N (CPE-¿N), which is a splice variant of CPE that has neuroprotective effects on embryonic neurons. CPE-¿N is transiently expressed in mouse embryos from embryonic day 5.5 to postnatal day 1. It is expressed in embryonic neurons, but not in 3 week or older mouse brains, suggesting a function primarily in utero. CPE-¿N expression was up-regulated in embryonic hippocampal neurons in response to dexamethasone treatment. CPE-¿N transduced into rat embryonic cortical and hippocampal neurons protected them from glutamate- and H2O2-induced cell death. When transduced into embryonic cortical neurons, CPE-¿N was found in the nucleus and enhanced the transcription of FGF2 mRNA. Embryonic cortical neurons challenged with glutamate resulted in attenuated FGF2 levels and cell death, but CPE-¿N transduced neurons treated in the same manner showed increased FGF2 expression and normal viability. This neuroprotective effect of CPE-¿N was mediated by secreted FGF2. Through receptor signaling, FGF2 activated the AKT and ERK signaling pathways, which in turn increased BCL-2 expression. This led to inhibition of caspase-3 activity and cell survival.

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