![]() In addition, in the early 1980 s, the interplay between pre-mRNAs and the U1, U2, U4, U5, and U6 small nuclear ribonucleoproteins (snRNPs) started to be discussed (Lerner et al. The contrasting levels of calcitonin expression in rat medullary thyroid carcinoma lines were discovered to be related with alternative transcripts later observed to originate from the same gene and to encode different proteins (Rosenfeld et al. Splicing in endogenous genes was revealed in the beginning of the 1980s with the findings of calcitonin and immunoglobulin alternative transcripts in mammals (Liu et al. In the following year, Walter Gilbert suggested naming the segments included in and excluded from the mature mRNAs as “exons” and “introns”, respectively (Gilbert 1978). However, how is such a simple trick performed? Let us unravel the magic of alternative splicing.Īlternative splicing (AS) was first reported in 1977 by the laboratories of Richard Roberts and Philip Sharp, who observed that mammalian cells infected with adenovirus 2 in lytic stage produce mRNA sequences complementary to non-contiguous DNA segments, as confirmed by electron microscopic visualisation of these alternative transcripts hybridised with single-stranded fragments of the viral genome (Berget et al. However, the trick is straightforward: it is a simple unit rearrangement of the gene sequence. The results are intriguing: some of these transcripts are almost identical, and others are so unique as to exert antagonising functions. From a single gene, multiple RNA products emerge. ![]() The final act of the spliceosome, however, is yet to be fully revealed, as more knowledge is needed regarding the complex regulatory network that coordinates alternative splicing and how its dysfunction leads to disease.Ĭonsider a magic trick, one that spans millions and millions of years, performed by a world-class magician known as the spliceosome. We also focus on the possibilities that splicing modulation therapies open for the future of personalized medicine, along with the leading techniques in this field. We discuss, on one hand, the essential role of alternative splicing in assuring tissue function, diversity, and swiftness of response in these systems or tissues, and on the other hand, what goes wrong when its regulatory mechanisms fail. In this review, we aim to bring the splicing machinery on stage and raise the curtain on its mechanisms and regulation throughout several systems and tissues of the human body, from neurodevelopment to the interactions with the human microbiome. ![]() A fine control of the isoform balance is, therefore, needed throughout developmental stages and adult tissues or physiological conditions and it does not come as a surprise that several diseases are caused by its deregulation. ![]() The differences between alternative isoforms may be subtle but enough to change the function or localization of the translated proteins. Alternative pre-mRNA splicing is a tightly controlled process conducted by the spliceosome, with the assistance of several regulators, resulting in the expression of different transcript isoforms from the same gene and increasing both transcriptome and proteome complexity.
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