Figure 2.

Switching MBNL1 on and off: the e1 loop. Upper panel (a) shows schematic representation of e1 splicing in MBNL1 pre-mRNA depending on transcription initiation start site T1 (left), T2 (middle) and T3 (right). T1- and T3-derived MBNL1 transcripts exhibit always skipped or included e1, respectively, independent of MBNL1. In contrast, T2-derived MBNL1 transcripts are subject to MBNL-dependent e1-splicing and feedback loop regulation outlined in lower panel (b). T2-derived MBNL1 transcripts are subject to MBNL-dependent e1-splicing. Fully functional MBNL1 protein translated from e1-containing MBNL1 mRNAs switches off its own expression by prompting e1 exclusion from MBNL1 pre-mRNA (exOFF). This results in MBNL1 proteins with compromised splicing activity and stability due to the absence of ZnF1/2. Truncated MBNL1 is no longer able to hinder e1 inclusion into mature mRNA, thus switching back the expression of the fully functional e1-containing MBNL1 (exON). Similarly, functional depletion of MBNL in DM, caused by sequestration on expanded C/CUG repeats, hinders MBNL1 splicing activity resulting in e1 inclusion and increased production of a fully functional MBNL1 (CNBP/DMPK C/CUG-expanded transcripts folding into toxic hairpin structures are indicated). Note, however, that in DM, the e1 feedback loop based on activation of e1 inclusion is overtaxed with time, depending on the length of sequestering C/CUG repeats and their somatic expansion. Orange and blue rectangles represent MBNL1 exons (numbered), and translation start sites (AUG) in specific splice-isoforms (+e1 or –e1) are indicated. MBNL1 proteins are depicted as large blue circles with ZnF1/2 and ZnF3/4 shown as smaller orange and purple circles, respectively. Truncated MBNL1 with compromised stability is shown as fading blue circles. Arrows point to direction of the e1-feedback loop. The model shown in a and b is based on our recently published data³.