Elsevier

Progress in Neurobiology

Volume 65, Issue 3, October 2001, Pages 289-308
Progress in Neurobiology

Alternative RNA splicing in the nervous system

https://doi.org/10.1016/S0301-0082(01)00007-7Get rights and content

Abstract

Tissue-specific alternative splicing profoundly effects animal physiology, development and disease, and this is nowhere more evident than in the nervous system. Alternative splicing is a versatile form of genetic control whereby a common pre-mRNA is processed into multiple mRNA isoforms differing in their precise combination of exon sequences. In the nervous system, thousands of alternatively spliced mRNAs are translated into their protein counterparts where specific isoforms play roles in learning and memory, neuronal cell recognition, neurotransmission, ion channel function, and receptor specificity. The essential nature of this process is underscored by the finding that its misregulation is a common characteristic of human disease. This review highlights the current views of the biological phenomenon of alternative splicing, and describes evidence for its intricate underlying biochemical mechanisms. The roles of RNA binding proteins and their tissue-specific properties are discussed. Why does alternative splicing occur in cosmic proportions in the nervous system? How does it affect integrated cellular functions? How are region-specific, cell-specific and developmental differences in splicing directed? How are the control mechanisms that operate in the nervous system distinct from those of other tissues? Although there are many unanswered questions, substantial progress has been made in showing that alternative splicing is of major importance in generating proteomic diversity, and in modulating protein activities in a temporal and spatial manner. The relevance of alternative splicing to diseases of the nervous system is also discussed.

Section snippets

Perspectives

Promptly after the discovery of RNA splicing in 1977, the question, ‘why genes in pieces?’, was addressed by a proposal for the generation of multiple mRNAs, and consequently multiple protein functions, from a single gene (Gilbert, 1978), presently termed alternative RNA splicing. It is evident that even a small change in the coding region of the mRNA can lead to a substantial switch in protein function, and that alternative splicing is used extensively as a way of increasing proteomic

Neurotransmission: neurotransmitter receptors and ion channels

Alternative splicing generates much of the enormous diversity needed in the proteins involved in forming specific synaptic connections and in mediating synaptic transmission. A single Purkinje neuron in mammalian brain may have as many as 100 000 synapses, which allows the cell to receive and integrate information from different neurons. Although the properties of each of these synapses will vary, each is dependent on numerous proteins involved in neurotransmitter reception and the release and

Cell type and developmental variations

How complex is the machinery for alternative splicing regulation in the nervous system? Are these regulatory mechanisms intrinsically different from those of other tissues? What determines tissue and cell type specificity? Many transcripts have been shown to undergo changes in splicing during neuronal development or to be alternatively spliced in different brain regions. To a limited extent, differences in alternative splicing at the level of individual cells in the brain have been examined

Alternative splicing abnormalities associated with human disease

More than a dozen cancers and inherited diseases in humans (and mice) are associated with abnormalities in alternative splicing. Disease pathology involving effects on the nervous system or on nervous system transcripts is conspicuously represented in these examples (Table 1, bold type). These abnormalities alter the abundance, location, or timing of a normally expressed mRNA isoform. In some cases, clearly defined cis-mutations can explain changes in splicing pattern, but where no cis-mutation

Conclusions

Alternative splicing affects protein function in the nervous system in a remarkably interesting variety of ways. It is apparent from the work reviewed here that the control mechanisms that specify tissue, cell and developmental changes in alternative splicing remain poorly understood despite progress in identifying regulatory elements and their RNA binding proteins. Neuron-specific splicing events are controlled by highly complex arrays of positive and negative RNA elements. These allow for

Acknowledgements

The authors acknowledge support from Howard Hughes Medical Institute and a grant from the National Institutes of Health to Douglas L. Black (RO1 GM49662).

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