Alternative Splicing: Cell‐type‐specific and Developmental Control

Abstract

Alternative splicing is a process that allows individual genes to produce multiple functionally distinct protein isoforms. The production of alternatively spliced isoforms is usually controlled in a cell type or developmentally regulated manner.

Keywords: RNA splicing; intron; gene expression; isoforms

Figure 1.

Modes of alternative splicing. (a) Retained intron, (b) competing 3′‐splice sites, (c) competing 5′‐splice sites, (d) alternative promoters, (e) alternative 3′‐end processing sites, (f) cassette exons, (g) mutually exclusive exons. Splicing patterns are illustrated by the diagonal black lines. Exons are denoted by the rectangles. Blue exons are constitutive; alternatively spliced segments are shown by the red boxes. Promoters are indicated by arrows and polyadenylation sites by ‘A’.

Figure 2.

Examples of complex transcription units. Four examples are given of genes that illustrate varying degrees of complexity in their alternative splicing patterns. (a) The P‐element transposase of Drosophila has a third intron that remains in the mRNA of somatic cells, but is spliced in germline cells yielding antagonistic products. (b) The adenovirus E1a transcription unit undergoes alternative splicing from three 5′‐splice sites to a common 3′‐splice site. Splicing to the proximal 13S site predominates in early infection, whereas the outer 9S site is favoured in late infection (c) α‐Tropomyosin produces at least nine isoforms with varying cell type specificities, through alternative promoters (internal promoter used only in nonmuscle cells) (A), two pairs of internal mutually exclusive exons (exon 2 only used in smooth muscle cells, exon 3 elsewhere) (B) and a complex set of alternative 3′‐end exons (exon 13 used in most cells, exon 11 is striated muscle specific, exon 12 used in striated muscle and brain) (C). (d) Protein 4.1 pre‐mRNA has two competing 3′‐splice sites on exon 2 (A), and 12 cassette exons, allowing for combinatorial splicing (B). Within each group of cassette exons, the black diagonal lines illustrate complete exon inclusion or skipping. The other potential patterns of exon inclusion are shown between the dotted lines. The gene can potentially produce more than 8000 splice variants.

Figure 3.

Regulation of sexual identity in Drosophila by a cascade of regulated splicing events. The sxl gene is the master control gene that determines sexual differentiation. It receives the primary signal from the ratio of autosomes to X‐chromosomes (X:A ratio), by activating an embryonic promoter at exon e1 in response to X:A = 1 (female). When the adult promoter is activated the presence of SXL protein ensures that exon 3, which contains stop codons, is skipped, leading to more SXL production. SXL negatively regulates exon 3 in its own pre‐mRNA, a proximal 3′‐splice site in tra intron 1 and an intron in the 5′‐UTR of msl2, thereby switching on sxl and tra, but switching off msl2. In males, MSL‐2 acts to increase the expression of X‐linked genes in the process of X‐chromosome dosage compensation. TRA acts as a positive regulator of a 3′‐splice site in exon 4 of dsx, and of a 5′‐splice site in exon 2 of fru. In each case it does this by binding with other proteins to a splicing enhancer sequence (shown in black). dsx and fru both express sex‐specific transcription factor variants that control somatic cell differentiation and sexual behaviour and orientation.

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Further Reading

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Lopez AJ (1995) Developmental role of transcription factor isoforms generated by alternative splicing. Developmental Biology 172: 396–411.

Lopez AJ (1998) Alternative splicing of pre‐mRNA: developmental consequences and mechanisms of regulation. Annual Review of Genetics 32: 279–305.

Maniatis T and Tasic B (2002) Alternative pre‐mRNA splicing and proteome expansion in metazoans. Nature 418: 236–243.

Smith CWJ and Valcárcel J (2000) Alternative pre‐mRNA splicing: the logic of combinatorial control. Trends in Biochemical Sciences 25: 381–388.

Stamm S (2003) Signals and their transduction pathways regulating alternative splicing: a new dimension to the human genome. Human Molecular Genetics 11: 2409–2416.

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Valcárcel, Juan, and Smith, Christopher WJ(Jan 2006) Alternative Splicing: Cell‐type‐specific and Developmental Control. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0003835]