title: FMRP targets distinct mRNA sequence elements to regulate protein expression.
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.
authors.affiliation: Howard Hughes Medical Institute, Laboratory of RNA Molecular Biology, The Rockefeller University, New York, New York 10065, USA.
authors.forename: Manuel
authors.initials: M
authors.lastname: Ascano
authors.forename: Neelanjan
authors.initials: N
authors.lastname: Mukherjee
authors.forename: Pradeep
authors.initials: P
authors.lastname: Bandaru
authors.forename: Jason B
authors.initials: JB
authors.lastname: Miller
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Nusbaum
authors.forename: David L
authors.initials: DL
authors.lastname: Corcoran
authors.forename: Christine
authors.initials: C
authors.lastname: Langlois
authors.forename: Mathias
authors.initials: M
authors.lastname: Munschauer
authors.forename: Scott
authors.initials: S
authors.lastname: Dewell
authors.forename: Markus
authors.initials: M
authors.lastname: Hafner
authors.forename: Zev
authors.initials: Z
authors.lastname: Williams
authors.forename: Uwe
authors.initials: U
authors.lastname: Ohler
authors.forename: Thomas
authors.initials: T
authors.lastname: Tuschl
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics / Q000378:metabolism; D003432:Cross-Linking Reagents; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008969:Molecular Sequence Data; D005810:Multigene Family; D009154:Mutation; D010053:Ovary / Q000378:metabolism / Q000473:pathology; D014176:Protein Biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D038621:Regulatory Sequences, Ribonucleic Acid / Q000235:genetics*; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction; D013379:Substrate Specificity
chemical_list: D003432:Cross-Linking Reagents; D051860:Fragile X Messenger Ribonucleoprotein 1; D012333:RNA, Messenger; D038621:Regulatory Sequences, Ribonucleic Acid; C497683:FMR1 protein, human; C497684:Fmr1 protein, mouse