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FMRP targets distinct mRNA sequence elements to regulate protein expression

Item Type:Article
Title:FMRP targets distinct mRNA sequence elements to regulate protein expression
Creators Name:Ascano, M. and Mukherjee, N. and Bandaru, P. and Miller, J.B. and Nusbaum, J.D. and Corcoran, D.L. and Langlois, C. and Munschauer, M. and Dewell, S. and Hafner, M. and Williams, Z. and Ohler, U. and Tuschl, T.
Abstract:Fragile X syndrome (FXS) is a multi-organ disease that leads to mental retardation, macro-orchidism in males and premature ovarian insufficiency in female carriers. FXS is also a prominent monogenic disease associated with autism spectrum disorders (ASDs). FXS is typically caused by the loss of fragile X mental retardation 1 (FMR1) expression, which codes for the RNA-binding protein FMRP. Here we report the discovery of distinct RNA-recognition elements that correspond to the two independent RNA-binding domains of FMRP, in addition to the binding sites within the messenger RNA targets for wild-type and I304N mutant FMRP isoforms and the FMRP paralogues FXR1P and FXR2P (also known as FXR1 and FXR2). RNA-recognition-element frequency, ratio and distribution determine target mRNA association with FMRP. Among highly enriched targets, we identify many genes involved in ASD and show that FMRP affects their protein levels in human cell culture, mouse ovaries and human brain. Notably, we discovered that these targets are also dysregulated in Fmr1(-/-) mouse ovaries showing signs of premature follicular overdevelopment. These results indicate that FMRP targets share signalling pathways across different cellular contexts. As the importance of signalling pathways in both FXS and ASD is becoming increasingly apparent, our results provide a ranked list of genes as basis for the pursuit of new therapeutic targets for these neurological disorders.
Keywords:RNA Metabolism, RNA-Binding Proteins, RNA, Diseases of the Nervous System, Animals, Mice
Source:Nature
ISSN:0028-0836
Publisher:Nature Publishing Group (U.K.)
Volume:492
Number:7429
Page Range:382-386
Date:20 December 2012
Official Publication:https://doi.org/10.1038/nature11737
PubMed:View item in PubMed

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