Alternative Pre-mRNA Splicing and Neuronal Function
The protein output of a gene is often regulated by splicing the primary RNA transcript into multiple mRNAs that differ in their coding exon sequences. These alternative splicing patterns are found in all kinds of genes and tissues. However, in the nervous
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The protein output of a gene is often regulated by splicing the primary RNA transcript into multiple mRNAs that differ in their coding exon sequences. These alternative splicing patterns are found in all kinds of genes and tissues. However, in the nervous system, proteins involved in two processes show particularly high levels of molecular diversity created by alternative splicing. These are proteins that determine the formation of neuronal connections during development and proteins that mediate cell excitation. Although some systems of splicing are highly complex, work on simpler model systems has started to identify the molecular components that determine these splicing switches. This review describes how alternative splicing is central to the control of neuronal function, and what is currently known about its mechanisms of regulation. How errors in splicing might contribute to diseases of the nervous system is also discussed.
1 Introduction The recent genomic description of -35,000 human genes and the earlier Drosophila genome sequence with -13,600 genes generated much discussion
of how a complex organism can be described by so few genes (Adams et al. 2000; Claverie 2001; Consortium 2001; Venter et al. 2001). It is clear that the protein complexity of an organism far outstrips the number of transcription units (Black 2000; Graveley 2001). The most common means of producing multiple proteins from one gene is through the alternative splicing of the gene's pre-mRNA. The processing of a primary gene transcript can be altered in the inclusion of exons, or the position of individual splice sites or polyadenylation sites to produce a variety of transcripts that differ in their encoded polypeptides (Fig. I}. Such mRNA sequence alterations make crucial changes in protein activity that are precisely regulated by the cellular environment. Alternative splicing is particularly common in the mammalian nervous system. Proteins Howard Hughes Medical Institute, University of California, Los Angeles, MRL 5-748,675 Charles E. Young Dr. South, Los Angeles, California 90095, USA 2 Howard Hughes Medical Institute and Department of Biological Sciences, University of Pittsburgh, 4249 Fifth Avenue, Pittsburgh, Pennsylvania 15260, USA
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Progress in Molecular and Subcellular Biology, Vol. 31 Philippe Jeanteur (Ed.) © Springer-Verlag Berlin Heidelberg 2003
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D.L. Black and P.J. Grabowski
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Fig. lA-D. Four common patterns of alternative splicing. White boxes represent constitutive exons present in every mRNA product. Gray boxes represent optional sequences that are included or excluded from the mRNA depending on the conditions. Patterns of alternative splicing include: A cassette exon; B alternative 3' splice sites; C alternative 5' splice sites; D alternative 3' splice sites combined with alternative polyadenylation sites. These patterns can occur singly or in combination. Other patterns of alternative splicing are not shown
involved in all aspects of neuronal developmen
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