FMRP targets distinct mRNA sequence elements to regulate protein expression.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Ascano, M; Mukherjee, N; Bandaru, P; Miller, JB; Nusbaum, JD; Corcoran, DL; Langlois, C; Munschauer, M; Dewell, S; Hafner, M; Williams, Z; Ohler, U; Tuschl, T

Published Date

  • December 20, 2012

Published In

Volume / Issue

  • 492 / 7429

Start / End Page

  • 382 - 386

PubMed ID

  • 23235829

Pubmed Central ID

  • 23235829

Electronic International Standard Serial Number (EISSN)

  • 1476-4687

Digital Object Identifier (DOI)

  • 10.1038/nature11737

Language

  • eng

Conference Location

  • England