FMRP modulates neural differentiation through m6A-dependent mRNA nuclear export.
Open accessAbstract
N 6 -methyladenosine (m 6 A) modification of mRNA is emerging as a vital mechanism regulating RNA function. Here, we show that fragile X mental retardation protein (FMRP) reads m 6 A to promote nuclear export of methylated mRNA targets during neural differentiation. Fmr1 knockout (KO) mice show delayed neural progenitor cell cycle progression and extended maintenance of proliferating neural progenitors into postnatal stages, phenocopying methyltransferase Mettl14 conditional KO (cKO) mice that have no m 6 A modification. RNA-seq and m 6 A-seq reveal that both Mettl14 cKO and Fmr1 KO lead to the nuclear retention of m 6 A-modified FMRP target mRNAs regulating neural differentiation, indicating that both m 6 A and FMRP are required for the nuclear export of methylated target mRNAs. FMRP preferentially binds m 6 A-modified RNAs to facilitate their nuclear export through CRM1. The nuclear retention defect can be mitigated by wild-type but not nuclear export-deficient FMRP, establishing a critical role for FMRP in mediating m 6 A-dependent mRNA nuclear export during neural differentiation.
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Delayed cell cycle progression and extended maintenance of immature proliferating neural progenitor cells are found in both human and mouse FXS models.
“Delayed cell cycle progression and extended maintenance of immature proliferating neural progenitor cells (NPCs) are found in both human and mouse FXS models (Edens et al., 2019; Raj et al., 2021).”
From Astrocytes in fragile X syndrome (2024) · cites this paper as Edens et al., 2019
The Results and Discussion report delayed cell-cycle progression and prolonged maintenance of proliferating neural progenitors in Fmr1-knockout mice. This paper does not establish the same findings in human FXS models, so it supports the mouse portion of the sentence but not the claim about both species. (LLM, conf=0.88)
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Cites
N6-methyladenosine-dependent regulation of messenger RNA stability
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“…loss of Fmr1 has been associated with abnormalities in cortical development and dendritic spine formation, which may contribute to aberrant learning and behavior in fragile X syndrome (Castrén et al., 2005; La Fata et al., 2014; Saffary and Xie, 2011; Shen et al., 2019; Tervonen et al., 2009).”
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“Consistent with our observations, alterations of layer-specific neuron migration and localization have been found in Fmr1KO mice (La Fata et al., 2014; Tervonen et al., 2009).”
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- Authors
- Edens, B. M., Vissers, C., Su, J., Arumugam, S., Xu, Z., Shi, H., Miller, N., Rojas Ringeling, F., Ming, G.-L., He, C., Song, H., & Ma, Y. C.
- Affiliations
- Northwestern University (US)
- Johns Hopkins University (US)
- University of Pennsylvania (US)
- University of Chicago (US)
- Corresponding author
- Song, Hongjun
- Ma, Yongchao C.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2019-07
- Volume
- 28
- Issue
- 4
- Pages
- 845-854.e5
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC6687293
- OpenAlex
- W2962876356
- Cited by
- 297
- References
- 9
- Citations by year
- 2026: 16 · 2025: 33 · 2024: 37 · 2023: 70 · 2022: 56 · 2021: 50 · 2020: 29 · 2019: 6
- FWCI
- 12.16
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- Funders
- Cure SMA
- Hartwell Foundation
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- 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
- Keywords
- FMRP, m6A RNA methylation, mRNA export, neuronal differentiation, neural progenitor cells, METTL14, CRM1, fragile X syndrome, Fmr1 knockout mice, RNA methylation, cell cycle progression
- MeSH terms
- Exportin 1 Protein, Adenosine, Animals, Animals, Newborn, Cell Cycle, Cell Differentiation, Cerebral Cortex, Neurons, RNA, Messenger, Gene Deletion, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Active Transport, Cell Nucleus, Karyopherins, RNA Transport, Cell Proliferation, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1, Neural Stem Cells
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