Cell-type specific dysregulation of RNA alternative splicing in short tandem repeat mouse knockin models of myotonic dystrophy

Short tandem repeats (STRs) are prone to expansion mutations that cause multiple hereditary neurological and neuromuscular diseases. To study pathomechanisms using mouse models that recapitulate the tissue specificity and developmental timing of an STR expansion gene, we used rolling circle amplification and CRISPR/Cas9-mediated genome editing to generate Dmpk CTG expansion (CTGexp) knockin models of myotonic dystrophy type 1 (DM1). We demonstrate that skeletal muscle myoblasts and brain choroid plexus epithelial cells are particularly susceptible to Dmpk CTGexp mutations and RNA mis-splicing. Our results implicate dysregulation of muscle regeneration and cerebrospinal fluid homeostasis as early pathogenic events in DM1. Overall design: RNAseq profiles were generated for tibialis anterior, differentiated myotubes and choroid plexus from either WT mice, or mice containing CTG repeat expansions as indicated, e.g.Dmpk 480 allele includes 480 CTG repeats.