Regulatory mechanisms of neuronal apoptosis by necdin/MAGE proteins

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We have studied the roles of necdin/MAGE family members in neuronal death (apoptosis), and the following results were obtained.1. Both necdin and its homologous protein MAGE-G1 (or necdin-like 2) bound to the proapoptotic proteins E2F1 transcription factor and p75 death receptor, and regulated neuronal apoptosis induced by these proteins.2. Necdin bound to the nerve growth factor (NGF) receptors TrkA and p75, and potentiated the activation of intraneuronal survival signals evoked by NGF.3. In necdin-deficient mice, apoptosis of NGF-dependent sensory neurons was augmented as a result of the attenuated NGF signaling. These mice displayed a high tolerance to thermal pain.4. Necdin formed a ternary complex with the homeodomain protein Dlx2 and the proapoptotic MAGE protein MAGE-D1. As Dlx2 promotes differentiation of forebrain GABAergic neurons, the number of these neurons decreased in necdin-deficient mice.5. In the cerebellar granule neurons of necdin-deficient mice, activation of proapoptotic E2F1 and apoptosis were augmented.These results suggest that necdin and necdin-related MAGE proteins suppress neuronal apoptosis to promote their survival. The present findings provide valuable insights into the molecular pathogenesis of the genomic imprinting-associated disorder Prader-Willi syndrome.