FMRP targets distinct mRNA sequence elements to regulate protein expression

Manuel Ascano, Neelanjan Mukherjee, Pradeep Bandaru, Jason B. Miller, Jeffrey D. Nusbaum, David L. Corcoran, Christine Langlois, Mathias Munschauer, Scott Dewell, Markus Hafner, Zev Williams, Uwe Ohler () and Thomas Tuschl ()
Additional contact information
Manuel Ascano: Howard Hughes Medical Institute, Laboratory of RNA Molecular Biology, The Rockefeller University
Neelanjan Mukherjee: Institute for Genome Sciences and Policy, Duke University
Pradeep Bandaru: Howard Hughes Medical Institute, Laboratory of RNA Molecular Biology, The Rockefeller University
Jason B. Miller: Howard Hughes Medical Institute, Laboratory of RNA Molecular Biology, The Rockefeller University
Jeffrey D. Nusbaum: Howard Hughes Medical Institute, Laboratory of RNA Molecular Biology, The Rockefeller University
David L. Corcoran: Institute for Genome Sciences and Policy, Duke University
Christine Langlois: Program for Early and Recurrent Pregnancy Loss, Albert Einstein College of Medicine
Mathias Munschauer: Howard Hughes Medical Institute, Laboratory of RNA Molecular Biology, The Rockefeller University
Scott Dewell: Genomics Resource Center, The Rockefeller University
Markus Hafner: Howard Hughes Medical Institute, Laboratory of RNA Molecular Biology, The Rockefeller University
Zev Williams: Howard Hughes Medical Institute, Laboratory of RNA Molecular Biology, The Rockefeller University
Uwe Ohler: Institute for Genome Sciences and Policy, Duke University
Thomas Tuschl: Howard Hughes Medical Institute, Laboratory of RNA Molecular Biology, The Rockefeller University

Nature, 2012, vol. 492, issue 7429, 382-386

Abstract: 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.

Date: 2012
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DOI: 10.1038/nature11737

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