转录中介体复合物MED23亚基在神经轴突生长与突触可塑性中的作用研究

During development, diverse neuronal axons extend over long distances to make connections with targets. Pathological changes in neural circuitry are associated with many neurological diseases such as Congenital mental retardation and Epilepsy. Accumulating evidence implicates axon growth in the rearrangement and loss of neuronal connections during neurological disorders. However, the transcriptional program controlling the axon guidance and neural circuitry is poorly understood. Mediator complex is the molecular bridge between transcriptional factors and RNA polymerase II to control diverse gene programs in response to developmental signals. Here, we find that Mediator MED23 may play an important role in axon growth and neural circuitry. Neural stem cell specific Med23 deletion mice died 24 hours after birth and showed that cortical neurons failed to extend axonal tracts to target areas. Therefore, we will explore the transcriptional mechanism by analyzing the neural stem cell specific Med23 deletion mice and primary cortical cultured neurons. These studies will provide novel molecular understanding for axon growth and new therapeutic strategies for human neurodevelopmental disorders.

在神经发育过程中，不同的神经元通过将轴突延伸到目标区域来建立正确的突触联系。而神经回路一旦发生病变将会引起许多神经相关疾病，譬如先天性智力障碍和癫痫等。随着研究的深入，人们发现对轴突生长机制的研究是解决神经回路病变的关键因素。然而，目前对轴突导向与神经回路形成的转录调控机制知之甚少。转录中介体复合物(Mediator)是转录因子与RNA聚合酶II间传递信息的桥梁，能调控不同的基因表达，从而决定细胞命运。我们最近发现Mediator亚基MED23可能在轴突生长和神经回路建立的过程中起着非常重要的作用。神经干细胞特异性敲除Med23小鼠出生致死，并且大脑皮层的神经元不能将轴突顺利伸到目标区域。因此，我们拟通过解析神经干细胞特异性敲除Med23小鼠和原代皮层神经元细胞，研究MED23在轴突生长过程中的转录调控机制，为相关疾病提供新的治疗策略。