FMR1 targets distinct mRNA sequence elements to regulate protein expression

By M. Ascano, Neelanjan Mukherjee, Pradeep Bandaru, Jason B Miller, Jeff Nusbaum, David L. Corcoran, Christine R. Langlois, Mathias Munschauer, Scott B. Dewell, M. Hafner and 3 more. Nature, 2012

680 citations recorded by the source corpus.

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.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/7e65799fa2a52b8c7ec7c3d6b81b8e886d470a5f

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In Genetics

Chuan He

In Molecular Biology

Citations in the corpus

FMRP Modulates Neural Differentiation through m6A-Dependent mRNA Nuclear Export (2019, neutral): “As previous analyses have suggested that FMRP may bind to consensus RNA methylation motifs (Ascano et al., 2012; Edupuganti et al., 2017; Fu et al., 2014), we considered that FMRP could serve as an m 6 A reader to bind and interpret m 6 A to regulate RNA function.”
Where, when and how: context-dependent functions of RNA methylation writers, readers, and erasers (2019, background): “In the case of FMR1, it binds consensus RNA sequences of GGA and ACU similar to the m6A-containing sequence (Ascano et al., 2012; Edupuganti et al., 2017).”