Alternative pre-mRNA splicing in neurons: growing up and extending its reach

Abstract

Alternative pre-mRNA splicing determines the protein output of most neuronally expressed genes. Many examples have been described of protein function being modulated by coding changes in different mRNA isoforms. Several recent studies demonstrate that, through the coupling of splicing to other processes of mRNA metabolism, alternative splicing can also act as an on/off switch for gene expression. Other regulated splicing events may determine how an mRNA is utilized in its later cytoplasmic life by changing its localization or translation. These studies make clear that the multiple steps of post-transcriptional gene regulation are strongly linked. Together, these regulatory process play key roles in all aspects of the cell biology of neurons, from their initial differentiation, to their choice of connections, and finally to their function with mature circuits.

Keywords: RNA binding proteins; RNA localization; intron retention; nonsense-mediated mRNA decay; post-transcriptional gene regulation.

Figure 1

Patterns of alternative pre-mRNA splicing that affect gene expression in the mammalian nervous system. In the pre-mRNA, exons (boxes) are connected by introns (horizontal lines). Constitutive and alternative exons are blue and yellow boxes respectively. Exons undergo different patterns of joining to generate alternative mRNA isoforms. (a) Alternative pre-mRNA processing can produce transcripts encoding completely different proteins. (b) In many cases, alternative exons encode peptide segments that modify protein structure and activity. (c) Regulated alternative splicing coupled with the nonsense mediated mRNA decay (NMD) of one of the spliced forms can control overall expression of a gene. Stop codons are indicated by S in hexagons. (d) Regulated intron retention may inhibit nuclear export to control gene expression, or may affect subsequent cytoplasmic mRNA function. The retained intron is indicated by a yellow line.