The Open Neuropsychopharmacology Journal

2011, 1 : 6-18
Published online 2011 August . DOI: 10.2174/1876523800801010006
Publisher ID: TONEUROPPJ-1-6

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

Shin-Ju E. Chang , Samantha Chang-Lin , Donald C. Chang , Chen Pu Chang , Shi-Lung Lin and Shao-Yao Ying
Department of Cell & Neurobiology, Keck School of Medicine, University of Southern California, 1333 San Pablo Street, BMT-403, Los Angeles, California 90033, USA.

ABSTRACT

A new class of repeat-associated microRNA (ramRNA) is identified to hinder normal brain development in zebrafish. 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 zebrafish 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 deficiency of its protein FMRP. FMRP deficiency further causes neurite deformity and synaptic dysfunction in the hippocampal neurons essential for cognition and memory. These findings provide significant insights into the role of ramRNAs in the embryonic brain development.

Keywords:

MicroRNA (miRNA), CGG trinucleotide repeat, FMR1.