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REVIEWS
Alternative pre-mRNA splicing is a mechanism that controls the protein output of eukaryotic genes, and a major contributor to proteomic diversity1,2. This process of gene regulation is especially common for genes that are expressed in the nervous system3, where the production of particular protein isoforms helps to determine the properties of the many different types of neurons4,5.
Recent work has identified several important events during neuronal development that are controlled by alternative splicing, including aspects of cell-fate determination, axon guidance and synaptogenesis. In the mature nervous system, the splicing of products that determine cell excitation is dynamically regulated by various cellular inputs. There is also increasing recognition that some neurological and neuromuscular diseases are caused by errors in splicing spinal muscular atrophy and frontotemporal dementia being two examples68. The
importance of individual splicing choices and of splicing regulators in nervous-system development and function is becoming clearer. In this Review, we describe a few of the many cellular processes in which splicing regulation is important, and discuss efforts to understand the molecular mechanisms that determine these splicing choices. We hope to provide an appreciation of the wide-ranging consequences of alternative splicing in neuronal cell biology.
General splicing mechanisms
The borders of pre-mRNA exons and introns are delineated by the 5 splice site at the upstream end of the intron and the 3 splice site at the downstream end. Alternative splicing involves changes in the choice of splice sites by the splicing apparatus and in the definition of introns9.
Intron excision and exon ligation are catalysed by a large ribonucleoprotein (RNP) complex called the spliceo-some, which is assembled onto each intron from five
small nuclear RNPs (snRNPs) and a large number of auxiliary proteins10 (BOX 1). The major class of spliceosome is made up of the U1, U2, U4, U5 and U6 snRNPs and excises nearly all introns in metazoans10. Although several interesting neuronal transcripts contain introns that are excised by the minor U12-dependent spliceosome, the two spliceosomes are very similar in their constituent parts and mechanisms of action.
Several processes alter spliceosome assembly and affect splice site choice. Spliceosome assembly initiates, and in some cases completes, intron excision during pre-mRNA synthesis, and the excision of some introns is strongly affected by transcription elongation rates11.
The...