FMRP targets distinct mRNA sequence elements to regulate protein expression
Open accessAbstract
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.
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Reduced ABCA1 in FXS astrocytes may reflect defective LXR/RXR signaling potentially caused by dysregulated RXRA and RXRB by the absence of FMRP.
“LXR/retinoic X receptor (RXR) ligands are known to stimulate ABCA1 expression and reduced ABCA1 in FXS astrocytes may reflect defective LXR/RXR signaling potentially caused by dysregulated RXRA and RXRB by the absence of FMRP48.”
From An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis (2023) · cites this paper as [48]
The Abstract and Results and Discussion (pages unavailable in our copy) state that FXS typically involves loss of FMRP and that FMRP affects the protein levels of its mRNA targets. They do not address RXRA, RXRB, LXR/RXR signaling, ABCA1, or FXS astrocytes; searches for those terms found no supporting passage. Thus the proposed pathway from FMRP loss to reduced astrocyte ABCA1 is not supported by this source. (LLM, conf=0.77)
Experimental — accuracy not yet measuredFMRP targets belong to multiple signaling and interconnected pathways such as PI3K-Akt-TSC-PTEN-mTOR and PI3K-RAS-MAPK, which have been linked to ASD through both underexpression and overexpression of genes in these pathways.
“This is consistent with evidence that FMRP targets belong to multiple signaling and interconnected pathways such as PI3K-Akt-TSC-PTEN-mTOR and PI3K-RAS-MAPK,59,60 which have been linked to ASD through both underexpression and overexpression of genes in these pathways.”
From Convergence of genes and cellular pathways dysregulated in autism spectrum disorders (2014) · cites this paper as [59]
PI3K is regulated by FMRP, is elevated in FXS mouse knockouts, and downregulation of this pathway has been shown to have therapeutic effect in ASD and FXS mouse models.
“PI3K, which is regulated by FMRP,59 is elevated in FXS mouse knockouts,62,63 and downregulation of this pathway has been shown to have therapeutic effect in ASD and FXS mouse models.”
From Convergence of genes and cellular pathways dysregulated in autism spectrum disorders (2014) · cites this paper as [59]
MIA-downregulated genes are highly enriched in FMRP targets (Darnell targets: OR=7.81, P=2.56e-127; Ascano targets: OR=2.07, P=1.75e-30).
“Across two FMRP target sets72, 73 (see Supplementary Table S1 for gene lists) we found that MIA-downregulated genes are highly enriched in FMRP targets (Darnell targets: OR=7.81, P=2.56e-127; Ascano targets: OR=2.07, P=1.75e-30).”
From Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder (2018) · cites this paper as [72]
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- Authors
- Ascano, M., Mukherjee, N., Bandaru, P., Miller, J. B., Nusbaum, J. D., Corcoran, D. L., Langlois, C., Munschauer, M., Dewell, S., Hafner, M., Williams, Z., Ohler, U., & Tuschl, T.
- Affiliations
- Howard Hughes Medical Institute (US)
- Duke University (US)
- Albert Einstein College of Medicine (US)
- Rockefeller University (US)
- Corresponding author
- Ohler, Uwe
- Tuschl, Thomas
- ORCID
- Venue
- Nature
- Published
- 2012-12
- Volume
- 492
- Issue
- 7429
- Pages
- 382-386
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3528815
- OpenAlex
- W2089927164
- Cited by
- 701
- References
- 53
- Citations by year
- 2026: 23 · 2025: 32 · 2024: 30 · 2023: 42 · 2022: 59 · 2021: 53 · 2020: 68 · 2019: 62 · 2018: 61 · 2017: 56 · 2016: 57 · 2015: 56 · 2014: 64 · 2013: 37 · 2012: 1
- FWCI
- 30.36
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Simons Foundation Autism Research Initiative
- National Institute of Mental Health (R01MH080442)
- National Institute of General Medical Sciences (R01GM104962)
- National Center for Research Resources (UL1RR024143)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (K08HD068546, HD068546)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- FMRP, fragile X syndrome, RNA-binding proteins, autism spectrum disorder, FXR1, FXR2, premature ovarian insufficiency, Fmr1 knockout mice, brain function, signaling pathways, therapeutic target
- MeSH terms
- Animals, Base Sequence, Binding Sites, Brain, Child, Child Development Disorders, Pervasive, Cross-Linking Reagents, Female, Gene Expression Regulation, Multigene Family, Humans, Molecular Sequence Data, Mutation, Ovary, RNA, Messenger, Substrate Specificity, Protein Biosynthesis, Signal Transduction, Response Elements, Regulatory Sequences, Ribonucleic Acid, Immunoprecipitation, Mice, Fragile X Messenger Ribonucleoprotein 1, HEK293 Cells
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