Key result
CELF repression rescues CELF-dependent alternative splicing in preclinical models of myotonic dystrophy.
Why the study?
Myotonic dystrophy type 1 pathogenesis involves alternative splicing dysregulation via elevated CELF1, but no previous studies specifically targeted CELF1.
Does repressing CELF activity rescue alternative splicing defects in cell culture and transgenic mouse models of myotonic dystrophy type 1?
Does repressing CELF activity rescue alternative splicing defects in cell culture and transgenic mouse models of myotonic dystrophy type 1?
Repressing CELF activity can rescue CELF-dependent, but not CELF-independent, alternative splicing defects in models of myotonic dystrophy type 1.
Rescuing splicing via CELF repression in DM1 models; hypothesis-generating and requires human validation before any clinical consideration.
Myotonic dystrophy type 1 (DM1) is caused by the expansion of CUG repeats in the 3' UTR of DMPK transcripts. DM1 pathogenesis has been attributed in part to alternative splicing dysregulation via elevation of CUG-BP, Elav-like family member 1 (CELF1). Several therapeutic approaches have been tested in cells and mice, but no previous studies had specifically targeted CELF1. Here, we show that repressing CELF activity rescues CELF-dependent alternative splicing in cell culture and transgenic mouse models of DM1. CELF-independent splicing, however, remained dysregulated. These data highlight both the potential and limitations of targeting CELF1 for the treatment of DM1.
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Berger et al. (2012) studied Myotonic dystrophy type 1 (DM1). Repressing CELF activity was evaluated on CELF-dependent alternative splicing. Repressing CELF activity rescued CELF-dependent alternative splicing in cell culture and transgenic mouse models of DM1, though CELF-independent splicing remained dysregulated.
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