FMRP targets distinct mRNA sequence elements to regulate protein expression

Nature. 2012 Dec 20;492(7429):382-6. doi: 10.1038/nature11737. Epub 2012 Dec 12.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Base Sequence
  • Binding Sites
  • Brain / metabolism
  • Child
  • Child Development Disorders, Pervasive / genetics
  • Child Development Disorders, Pervasive / metabolism
  • Cross-Linking Reagents
  • Female
  • Fragile X Mental Retardation Protein / genetics*
  • Fragile X Mental Retardation Protein / metabolism*
  • Gene Expression Regulation / genetics*
  • HEK293 Cells
  • Humans
  • Immunoprecipitation
  • Mice
  • Molecular Sequence Data
  • Multigene Family
  • Mutation
  • Ovary / metabolism
  • Ovary / pathology
  • Protein Biosynthesis / genetics*
  • RNA, Messenger / genetics*
  • RNA, Messenger / metabolism
  • Regulatory Sequences, Ribonucleic Acid / genetics*
  • Response Elements / genetics
  • Signal Transduction
  • Substrate Specificity

Substances

  • Cross-Linking Reagents
  • FMR1 protein, human
  • Fmr1 protein, mouse
  • RNA, Messenger
  • Regulatory Sequences, Ribonucleic Acid
  • Fragile X Mental Retardation Protein

Associated data

  • GEO/GSE39686