Myotonic Dystrophy Type I (DM1) is a multi-system, autosomal dominant disorder due to expansion of a CTG repeat sequence in the 3'UTR of the DMPK gene. Repeat size correlates with age of onset and disease severity, with large repeats leading to congenital forms of DM1 associated with hypotonia and intellectual disability. In models of adult DM1, expanded CUG repeats lead to an RNA toxic gain of function at least in part mediated by sequestering specific RNA splicing proteins, most notably muscleblind related proteins (MBNL). However, the impact of CUG RNA repeat expression on early developmental processes is not well understood. To better understand early developmental processes in DM1, we utilized the zebrafish, Danio rerio, as a model system. Direct injection of (CUG)91 repeat-ontaining mRNA into single cell embryos induces toxicity in the nervous system and muscle during early development. These effects manifest as abnormal morphology, behavioral abnormalities, and broad transcriptional changes based on cDNA microarray analysis. Co-injection of zebrafish mbnl2 RNA suppresses (CUG)91 RNA toxicity and reverses the associated behavioral and transcriptional abnormalities. Taken together, these findings suggest that early expression of exogenously transcribed CUG repeat RNA can disrupt normal muscle and nervous system development and provides a new model for DM1 research that is amenable to small molecule therapeutic development.
- Received March 17, 2013.
- Accepted September 30, 2013.
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