The MicroRNA miR-124 Promotes Neuronal Differentiation by Triggering Brain-Specific Alternative Pre-mRNA Splicing

Makeyev, Eugene V.; Zhang, Jiangwen; Carrasco, Monica A.; Maniatis, Tom

doi:10.1016/j.molcel.2007.07.015

Cited by 1,395RNA Research and SplicingMicroRNA in disease regulationNeurogenesis and neuroplasticity mechanisms

The MicroRNA miR-124 Promotes Neuronal Differentiation by Triggering Brain-Specific Alternative Pre-mRNA Splicing

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Makeyev, Eugene V., Zhang, Jiangwen, Carrasco, Monica A., Maniatis, Tom·2007·Molecular Cell

DOI 10.1016/j.molcel.2007.07.015PMC PMC3139456

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Abstract

Both microRNAs and alternative pre-mRNA splicing have been implicated in the development of the nervous system (NS), but functional interactions between these two pathways are poorly understood. We demonstrate that the neuron-specific microRNA miR-124 directly targets PTBP1 (PTB/hnRNP I) mRNA, which encodes a global repressor of alternative pre-mRNA splicing in nonneuronal cells. Among the targets of PTBP1 is a critical cassette exon in the pre-mRNA of PTBP2 (nPTB/brPTB/PTBLP), an NS-enriched PTBP1 homolog. When this exon is skipped, PTBP2 mRNA is subject to nonsense-mediated decay (NMD). During neuronal differentiation, miR-124 reduces PTBP1 levels, leading to the accumulation of correctly spliced PTBP2 mRNA and a dramatic increase in PTBP2 protein. These events culminate in the transition from non-NS to NS-specific alternative splicing patterns. We also present evidence that miR-124 plays a key role in the differentiation of progenitor cells to mature neurons. Thus, miR-124 promotes NS development, at least in part by regulating an intricate network of NS-specific alternative splicing.

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MTAG benchmark against height and BMI added no significant loci to the list of ASD-only significant associations.
“Moreover, we benchmarked against MTAG running two very large and heritable traits (height 74 , n=252,288, and BMI 24 , n=322,154) with no expected links to ASD and no significant loci were added to the list of ASD-only significant associations.”
From Identification of common genetic risk variants for autism spectrum disorder (2019) · cites this paper as [74]
The interplay between miRNAs and RBPs leads to global changes in gene expression in which miRNAs control expression of RBPs to regulate tissue-specific RNA processing decisions.
“The interplay between miRNAs and RBPs leads to global changes in gene expression in which miRNA(s) control expression of RBPs to regulate tissue-specific RNA processing decisions (Boutz et al. 2007; Makeyev et al. 2007; Kalsotra et al. 2010; van Kouwenhove et al. 2011; Misra et al. 2020)”
From ESRP2–microRNA-122 axis promotes the postnatal onset of liver polyploidization and maturation (2025) · cites this paper as Makeyev et al. 2007
miR-124 promotes neuronal differentiation, in part through targeting of a splicing factor.
“miR-124 promotes neuronal differentiation, in part through targeting of a splicing factor (Makeyev et al., 2007).”
From The Bifunctional microRNA miR-9/miR-9* Regulates REST and CoREST and Is Downregulated in Huntington's Disease (2008) · cites this paper as Makeyev et al., 2007
miR-124 promotes differentiation of neuronal progenitors to mature neurons by targeting small C-terminal domain phosphatase-1 and polypyrimidine tract-binding protein-1.
“It promotes differentiation of neuronal progenitors to mature neurons by targeting small C-terminal domain phosphatase-1 and polypyrimidine tract–binding protein-1 that repress expression of neuronal genes in non-neuronal cells18,20,40.”
From MicroRNA-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages via the C/EBP-α–PU.1 pathway (2011) · cites this paper as [20]
Repression of Ptbp2 exon 10 by PTBP1 leads to nonsense-mediated mRNA decay of the Ptbp2 transcript and prevents its expression in PTBP1+ cells.
“The repression of exon 10 leads to nonsense-mediated mRNA decay (NMD) of the Ptbp2 transcript and prevents its expression in PTBP1+ cells15,20,21.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [15]

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Authors: Makeyev, E. V., Zhang, J., Carrasco, M. A., & Maniatis, T.
Affiliations: Harvard University (US)
Corresponding author: Maniatis, Tom
ORCID: Makeyev, Eugene V.
Zhang, Jiangwen
Maniatis, Tom
Venue: Molecular Cell
Publisher: Elsevier BV
Published: 2007-08
Volume: 27
Issue: 3
Pages: 435-448
ISSN: 1097-2765 (ISSN-L)
DOI: 10.1016/j.molcel.2007.07.015
PMC: PMC3139456
OpenAlex: W2038874091
Cited by: 1,395
References: 61
Citations by year: 2026: 26 · 2025: 51 · 2024: 50 · 2023: 60 · 2022: 47 · 2021: 61 · 2020: 67 · 2019: 63 · 2018: 72 · 2017: 70 · 2016: 92 · 2015: 92 · 2014: 108 · 2013: 109 · 2012: 92
FWCI: 32.88
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 2177 d)
Locations: Molecular Cell (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
Funders: National Institute of Neurological Disorders and Stroke (R01NS043915)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords: miR-124, neuronal differentiation, alternative splicing, PTBP1, PTBP2, nonsense-mediated mRNA decay, microRNA target regulation, brain development, neural progenitor cells
MeSH terms: Animals, Brain, Cell Differentiation, Cells, Cultured, Exons, Humans, Mitosis, Nerve Tissue Proteins, Neuroblastoma, Neurons, RNA Precursors, RNA Processing, Post-Transcriptional, RNA, Messenger, Transfection, Alternative Splicing, Gene Expression Regulation, Developmental, Heterogeneous-Nuclear Ribonucleoproteins, MicroRNAs, Polypyrimidine Tract-Binding Protein, Mice

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The MicroRNA miR-124 Promotes Neuronal Differentiation by Triggering Brain-Specific Alternative Pre-mRNA Splicing

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