Alternative splicing regulation by Muscleblind proteins: from development to disease

Regulated use of exons in pre-mRNAs, a process known as alternative splicing, strongly contributes to proteome diversity. Alternative splicing is finely regulated by factors that bind specific sequences within the precursor mRNAs. Members of the Muscleblind (Mbl) family of splicing factors control critical exon use changes during the development of specific tissues, particularly heart and skeletal muscle. Muscleblind homologs are only found in metazoans from Nematoda to mammals. Splicing targets and recognition mechanisms are also conserved through evolution. In this recognition, Muscleblind CCCH-type zinc finger domains bind to intronic motifs in pre-mRNA targets in which the protein can either activate or repress splicing of nearby exons, depending on the localization of the binding motifs relative to the regulated alternative exon. In humans, the Muscleblind-like 1 (MBNL1) proteins play a critical role in hereditary diseases caused by microsatellite expansions, particularly myotonic dystrophy type 1 (DM1), in which depletion of MBNL1 activity through sequestration explains most misregulated alternative splicing events, at least in murine models. Because of the involvement of these proteins in human diseases, further understanding of the molecular mechanisms by which MBNL1 regulates splicing will help design therapies to revert pathological splicing alterations. Here we summarize the most relevant findings on this family of proteins in recent years, focusing on recently described functional motifs, transcriptional regulation of Muscleblind, regulatory activity on splicing, and involvement in human diseases.