神经元成熟需要戏剧性的形态和功能变化,但是控制这一过程的分子机制还没有得到很好的理解。这里,我们研究了Rbfox1,Rbfox2和Rbfox3蛋白的作用,一个在多种神经发育障碍中突变的组织特异性剪接调节因子家族。我们生成了Rbfox三重敲除(tKO)腹侧脊髓神经元,以定义在Rbfox调节下的替代外显子的综合网络,并研究其在发育中的神经元中的功能重要性。RbfoxtKO神经元在许多细胞骨架的选择性剪接中表现出缺陷,膜,和突触蛋白,并显示不成熟的电生理活动。轴突初始部分(AIS),对动作电位启动很重要的亚细胞结构,随着Rbfox的枯竭而减少。我们在ankyrinG中确定了Rbfox调节的剪接开关,AIS“相互作用枢纽”蛋白质,调节锚蛋白G-β血影蛋白亲和力和AIS组装。我们的数据表明,Rbfox调节的剪接程序在有丝分裂后神经元的结构和功能成熟中起着至关重要的作用。
Neuronal maturation requires dramatic morphological and functional changes, but the molecular mechanisms governing this process are not well understood. Here, we studied the role of Rbfox1, Rbfox2, and Rbfox3 proteins, a family of tissue-specific splicing regulators mutated in multiple neurodevelopmental disorders. We generated Rbfox triple knockout (tKO) ventral spinal neurons to define a comprehensive network of alternative exons under Rbfox regulation and to investigate their functional importance in the developing neurons. Rbfox tKO neurons exhibit defects in alternative splicing of many cytoskeletal, membrane, and synaptic proteins, and display immature electrophysiological activity. The axon initial segment (AIS), a subcellular structure important for action potential initiation, is diminished upon Rbfox depletion. We identified an Rbfox-regulated splicing switch in ankyrin G, the AIS \"interaction hub\" protein, that regulates ankyrin G-beta spectrin affinity and AIS assembly. Our data show that the Rbfox-regulated splicing program plays a crucial role in structural and functional maturation of postmitotic neurons.