TISSUE-SPECIFIC SPLICING OF 2 MUTUALLY EXCLUSIVE EXONS OF THE CHICKENBETA-TROPOMYOSIN PRE-MESSENGER-RNA - POSITIVE AND NEGATIVE REGULATIONS

Alternative splicing of premessenger RNA (pre-mRNA) is a widespread pr ocess used in higher eucaryotes to regulate gene expression. A single primary transcript can generate multiple proteins with distinct functi ons in a tissue-and/or developmental-specific manner A central questio n in alternative splicing concerns the selection of splice sites in di fferent cell environments. In this review, we present our results on t he alternative splicing of the chicken beta-tropomyosin gene which pro vides an interesting model for understanding mechanisms involved in sp lice site selection. The beta-tropomyosin gene contains in its central portion a pair of exons (6A and 6B) that are used mutually exclusivel y in a tissue and developmental stage-specific manner. Exon 6A is pres ent in mRNA of non-muscle and smooth muscle tissues while exon 6B is o nly present in mRNA of skeletal muscle. Regulation of both exons is ne cessary to ensure specific expression of beta-tropomyosin gene in non- muscle cells. Several cis-acting elements involved in the repression o f exon 6B and activation of exon 6A have been identified. In addition, we show that the tissue-specific choice of exon 6A is mediated throug h interaction with a specific class of splicing factors, the SR protei ns. In the last part of this review we will focus on possible mechanis ms needed to switch to exon 6B selection in skeletal muscle tissue. We propose that tissue-specific choice of exon 6B involves down regulati on of exon 6A and activation of exon 6B. A G-rich enhancer sequence do wnstream of exon 6B has been defined that is needed for efficient reco gnition of the exon 6B 5' splice site. Moreover, we suggest that alter ation of the ratio between proteins of the SR family contributes to ti ssue-specific splice site selection.