The Mechanisms by Which MBNL1 and MBNL2 Separate their Alternative-Splicing Functions

Alternative splicing factors regulate alternative exon repression or activation which allows one pre-mRNA to code for multiple protein isoforms. MBNL is a family of alternative splicing factors that is sequestered in myotonic dystrophy patients. MBNL1 and MBNL2 are highly similar proteins in the MBNL family, but knock-out of each protein in mouse has a different phenotype. The goal of this work is to study how MBNL1 and MBNL2 separate their alternative splicing functions. MBNL1 and MBNL2-dependent splicing was studied using splicing sensitive microarrays and RT-PCR of MBNL1 KO and MBNL2 KO mouse embryonic fibroblasts. Examples are shown of splicing events where MBNL1 and MBNL2 have unique contributions to alternative splicing are identified, as well as splicing events where MBNL1 and MBNL2 are dually-required. An example of threshold-dependent alternative splicing was discovered. Preliminary evidence suggests that auto-regulated exon 5 of MBNL2 could have a role in splicing regulation