Recent Advances in Understanding of Alternative Splicing in Neuronal Pathogenesis

The nervous system is an intricate and highly specialized network of neurons. Neuronal differentiation involves complex reprogramming of gene expression. Alternative splicing of precursor mRNAs increases the complexity of transcriptomes and diversifies protein functions at the post-transcriptional level. Indeed, alternative splicing plays an important role in neuronal differentiation, axon guidance, synaptogenesis, synaptic transmission, and plasticity. Because the delicate structure and function of neurons make them particularly susceptible to dysregulation of splicing, aberrant expression or function of splicing factors may cause neuronal disorders. Therefore, it is important to improve our understanding of the mechanisms and physiological functions of alternative splicing regulation in neurons. Regulation of alternative splicing primarily involves the binding of regulatory factors to specific cis-elements of precursor mRNAs, and interplay between splicing factors may lead to fine tuning of splicing regulation, thereby diversifying the cadre of mature products. In addition, transcription rate and the availability of the basal splicing machinery may also influence alternative splicing. Recently, our understanding of the mechanisms underlying alternative splicing have been advanced from studies of several neuronal splicing factors; these studies have utilized genetic knockout or disease models as well as genome-wide analysis of mRNA isoforms. In this chapter, we review current understanding of alternative splicing in neurons.