Repeat-Associated MicroRNAs Trigger Fragile X Mental Retardation- Like Syndrome in Zebrafish

A new class of repeat-associated microRNA (ramRNA) is identified to hinder normal brain development in ze- brafish. Previous studies have shown that small hairpin RNAs derived from the 5'-untranslational CGG/CCG trinucleotide repeat (r(CGG)) expansion of fragile X mental retardation gene 1, FMR1, may cause neuronal toxicity in fragile X mental retardation syndrome (FXS). However, their roles in FXS remain unclear. We report here that over-expression of a novel ramRNA species isolated from the fish FMR1 r(CGG) region triggers FXS-like neurodegeneration in a transgenic zebraf- ish model. Hyper-methylation of the FMR1 5'-r(CGG) region associated with ramRNA over-expression is central to this FXS-like etiology. Such an epigenetic modification results in the transcriptional inactivation of the FMR1 gene and defi- ciency of its protein FMRP. FMRP deficiency further causes neurite deformity and synaptic dysfunction in the hippocam- pal neurons essential for cognition and memory. These findings provide significant insights into the role of ramRNAs in the embryonic brain development.