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, Thomas Tuschl

Research output: Contribution to journalArticle

324 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)382-386
Number of pages5
JournalNature
Volume492
Issue number7429
DOIs
StatePublished - Dec 20 2012

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Fragile X Syndrome
Messenger RNA
Intellectual Disability
Ovary
Proteins
RNA
RNA-Binding Proteins
Nervous System Diseases
Genes
Protein Isoforms
Cell Culture Techniques
Binding Sites
Brain
Autism Spectrum Disorder
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Ascano, M., Mukherjee, N., Bandaru, P., Miller, J. B., Nusbaum, J. D., Corcoran, D. L., ... Tuschl, T. (2012). FMRP targets distinct mRNA sequence elements to regulate protein expression. Nature, 492(7429), 382-386. https://doi.org/10.1038/nature11737

FMRP targets distinct mRNA sequence elements to regulate protein expression. / Ascano, Manuel; Mukherjee, Neelanjan; Bandaru, Pradeep; Miller, Jason B.; Nusbaum, Jeffrey D.; Corcoran, David L.; Langlois, Christine; Munschauer, Mathias; Dewell, Scott; Hafner, Markus; Williams, Zev; Ohler, Uwe; Tuschl, Thomas.

In: Nature, Vol. 492, No. 7429, 20.12.2012, p. 382-386.

Research output: Contribution to journalArticle

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 2012, 'FMRP targets distinct mRNA sequence elements to regulate protein expression', Nature, vol. 492, no. 7429, pp. 382-386. https://doi.org/10.1038/nature11737
Ascano M, Mukherjee N, Bandaru P, Miller JB, Nusbaum JD, Corcoran DL et al. FMRP targets distinct mRNA sequence elements to regulate protein expression. Nature. 2012 Dec 20;492(7429):382-386. https://doi.org/10.1038/nature11737
Ascano, Manuel ; Mukherjee, Neelanjan ; Bandaru, Pradeep ; Miller, Jason B. ; Nusbaum, Jeffrey D. ; Corcoran, David L. ; Langlois, Christine ; Munschauer, Mathias ; Dewell, Scott ; Hafner, Markus ; Williams, Zev ; Ohler, Uwe ; Tuschl, Thomas. / FMRP targets distinct mRNA sequence elements to regulate protein expression. In: Nature. 2012 ; Vol. 492, No. 7429. pp. 382-386.
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