The inclusion of microexons by alternative splicing occurs frequently in neuronal proteins. The roles of these sequences are largely unknown, and changes in their degree of inclusion are associated with neurodevelopmental disorders¹. We have previously shown that decreased inclusion of a 24-nucleotide neuron-specific microexon in CPEB4, a RNA-binding protein that regulates translation through cytoplasmic changes in poly(A) tail length, is linked to idiopathic autism spectrum disorder (ASD)². Why this microexon is required and how small changes in its degree of inclusion have a dominant-negative effect on the expression of ASD-linked genes is unclear. Here we show that neuronal CPEB4 forms condensates that dissolve after depolarization, a transition associated with a switch from translational repression to activation. Heterotypic interactions between the microexon and a cluster of histidine residues prevent the irreversible aggregation of CPEB4 by competing with homotypic interactions between histidine clusters. We conclude that the microexon is required in neuronal CPEB4 to preserve the reversible regulation of CPEB4-mediated gene expression in response to neuronal stimulation.

选择性剪接包含微外显子经常发生在神经元蛋白中。这些序列的作用在很大程度上是未知的，它们包含程度的变化与神经发育障碍有关¹。我们之前已经表明，CPEB4 中 24 核苷酸神经元特异性微外显子的包含减少，CPEB4 是一种 RNA 结合蛋白，通过 poly （A） 尾长的细胞质变化调节翻译，与特发性自闭症谱系障碍 （ASD） 有关²。为什么需要这种微外显子以及其包含程度的微小变化如何对 ASD 相关基因的表达产生显性负效应尚不清楚。在这里，我们表明神经元 CPEB4 形成凝聚物，这些凝聚物在去极化后溶解，这是与从翻译抑制到激活的转变相关的转变。微外显子和组氨酸残基簇之间的异型相互作用通过与组氨酸簇之间的同型相互作用竞争来阻止 CPEB4 的不可逆聚集。我们得出结论，神经元 CPEB4 中需要微外显子来保持 CPEB4 介导的基因表达的可逆调节以响应神经元刺激。