Regulatory mechanisms of neuronal apoptosis by necdin/MAGE proteins

我们研究了necdin/法师家族成员在神经元死亡（细胞凋亡）中的作用，得到以下结果. necdin及其同源蛋白MAGE-G1（或necdin-like 2）与促凋亡蛋白E2 F1转录因子和p75死亡受体结合，调节这些蛋白诱导的神经元凋亡. Necdin与神经生长因子（NGF）受体TrkA和p75结合，增强NGF诱发的神经元内存活信号的激活.在necdin缺陷小鼠中，由于减弱的NGF信号传导，NGF依赖的感觉神经元的凋亡增加。这些小鼠表现出对热痛的高耐受性。Necdin与同源结构域蛋白Dlx 2和促凋亡法师蛋白MAGE-D1形成三元复合物。由于Dlx 2促进前脑GABA能神经元的分化，necdin缺陷小鼠中这些神经元的数量减少.在necdin缺陷小鼠的小脑颗粒神经元中，促凋亡E2 F1的激活和凋亡增强，这些结果表明necdin和necdin相关的法师蛋白抑制神经元凋亡以促进其存活。目前的研究结果提供了有价值的见解基因组印记相关疾病普拉德-威利综合征的分子发病机制。

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.