The Muscleblind family of proteins: an emerging class of regulators of developmentally programmed alternative splicing

Differentiation; Research in Biological Diversity
Maya PascualRuben Artero

Abstract

Alternative splicing is widely used to generate protein diversity and to control gene expression in many biological processes, including cell fate determination and apoptosis. In this review, we focus on the Muscleblind family of tissue-specific alternative splicing regulators. Muscleblind proteins bind pre-mRNA through an evolutionarily conserved tandem CCCH zinc finger domain. Human Muscleblind homologs MBNL1, MBNL2 and MBNL3 promote inclusion or exclusion of specific exons on different pre-mRNAs by antagonizing the activity of CUG-BP and ETR-3-like factors (CELF proteins) bound to distinct intronic sites. The relative activities of Muscleblind and CELF proteins control a key developmental switch. Defined transcripts follow an embryonic splice pattern when CELF activity predominates, whereas they follow an adult pattern when Muscleblind activity prevails. Human MBNL proteins show functional specializations. While MBNL1 seems to promote muscle differentiation, MBNL3 appears to function in an opposing manner inhibiting expression of muscle differentiation markers. MBNL2, on the other hand, participates in a new RNA-dependent protein localization mechanism involving recruitment of integrin alpha3 protein to focal adhesions. Both...Continue Reading

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