Alternative RNA splicing in the nervous system
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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